Pyrimidone derivatives

ABSTRACT

A pyrimidone derivative represented by the formula (I) or a salts thereof: 
                         
wherein R 1  represents an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group and the like; R 2  represents a hydrogen atom, hydroxyl group, an alkyl group, an alkenyl group and the like, R 3  represents a pyridyl group, and a medicament comprising said derivative or a salt thereof as an active ingredient which is used for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity such as Alzheimer disease.

TECHNICAL FIELD

The present invention relates to compounds that are useful as an activeingredient of a medicament for preventive and/or therapeutic treatmentof diseases caused by abnormal advance of tau protein kinase 1, such asAlzheimer disease and the like.

BACKGROUND ART

Alzheimer disease is progressive senile dementia, in which markedcerebral cortical atrophy is observed due to degeneration of nerve cellsand decrease of nerve cell number. Pathologically, numerous senileplaques and neurofibrillary tangles are observed in brain. The number ofpatients has been increased with the increment of aged population, andthe disease arises a serious social problem. Although various theorieshave been proposed, a cause of the disease has not yet been elucidated.Early resolution of the cause has been desired.

It has been known that the degree of appearance of two characteristicpathological changes of Alzheimer disease well correlates to the degreeof intellectual dysfunction. Therefore, researches have been conductedfrom early 1980's to reveal the cause of the disease through molecularlevel investigations of components of the two pathological changes.Senile plaques accumulate extracellularly, and amyloid β protein hasbeen elucidated as their main component (abbreviated as “Aβ” hereinafterin the specification: Biochem. Biophys. Res. Commun., 120, 885 (1984):EMBO J., 4, 2757 (1985); Proc. Natl. Acad. Sci. USA, 82, 4245 (1985)).In the other pathological change, i.e., the neurofibrillary tangles, adouble-helical filamentous substance called paired helical filament(abbreviated as “PHF” hereinafter in the specification) accumulateintracellularly, and tau protein, which is a kind ofmicrotubule-associated protein specific for brain, has been revealed asits main component (Proc. Natl. Acad. Sci. USA, 85, 4506 (1988); Neuron,1, 827 (1988)).

Furthermore, on the basis of genetic investigations, presenilins 1 and 2were found as causative genes of familial Alzheimer disease (Nature,375, 754 (1995); Science, 269, 973 (1995); Nature, 376, 775 (1995)), andit has been revealed that presence of mutants of presenilins 1 and 2promotes the secretion of Aβ (Neuron, 17, 1005 (1996); Proc. Natl. Acad.Sci. USA, 94, 2025 (1997)). From these results, it is considered that,in Alzheimer disease, Aβ abnormally accumulates and agglomerates due toa certain reason, which engages with the formation of PHF to cause deathof nerve cells. It is also expected that extracellular outflow ofglutamic acid and activation of glutamate receptor responding to theoutflow may possibly be important factors in an early process of thenerve cell death caused by ischemic cerebrovascular accidents (Sai-shinIgaku [Latest Medicine], 49, 1506 (1994)).

It has been reported that kainic acid treatment that stimulates the AMPAreceptor, one of glutamate receptor, increases mRNA of the amyloidprecursor protein (abbreviated as “APP” hereinafter in thespecification) as a precursor of Aβ (Society for Neuroscience Abstracts,17, 1445 (1991)), and also promotes metabolism of APP (The Journal ofNeuroscience, 10, 2400 (1990)). Therefore, it has been stronglysuggested that the accumulation of Aβ is involved in cellular death dueto ischemic cerebrovascular disorders. Other diseases in which abnormalaccumulation and agglomeration of Aβ are observed include, for example,Down syndrome, cerebral bleeding due to solitary cerebral amyloidangiopathy, Lewy body disease (Shin-kei Shinpo [Nerve Advance], 34, 343(1990); Tanpaku-shitu Kaku-san Koso [Protein, Nucleic Acid, Enzyme], 41,1476 (1996)) and the like. Furthermore, as diseases showingneurofibrillary tangles due to the PHF accumulation, examples includeprogressive supranuclear palsy, subacute sclerosing panencephaliticparkinsonism, postencephalitic parkinsonism, pugilistic encephalitis,Guam parkinsonism-dementia complex, Lewy body disease and the like(Tanpakushitu Kakusan Koso [Protein, Nucleic Acid, Enzyme], 36, 2(1991); Igaku no Ayumi [Progress of Medicine], 158, 511 (1991);Tanpakushitu Kakusan Koso [Protein, Nucleic Acid, Enzyme], 41, 1476(1996)).

The tau protein is generally composed of a group of related proteinsthat forms several bands at molecular weights of 48–65 kDa inSDS-polyacrylamide gel electrophoresis, and it promotes the formation ofmicrotubules. It has been verified that tau protein incorporated in thePHF in the brain suffering from Alzheimer disease is abnormallyphosphorylated compared with usual tau protein (J. Biochem., 99, 1807(1986); Proc. Natl. Acad. Sci. USA, 83, 4913 (1986)). An enzymecatalyzing the abnormal phosphorylation has been isolated. The proteinwas named as tau protein kinase 1 (abbreviated as “TPK1” hereinafter inthe specification), and its physicochemical properties have beenelucidated (Seikagaku [Biochemistry], 64, 308 (1992); J. Biol. Chem.,267, 10897 (1992)). Moreover, cDNA of rat TPK1 was cloned from a ratcerebral cortex cDNA library based on a partial amino acid sequence ofTPK1, and its nucleotide sequence was determined and an amino acidsequence was deduced (Japanese Patent Un-examined Publication [Kokai]No. 6-239893/1994). As a result, it has been revealed that the primarystructure of the rat TPK1 corresponds to that of the enzyme known as ratGSK-3 β (glycogen synthase kinase 3β, FEBS Lett., 325, 167 (1993)).

It has been reported that Aβ, the main component of senile plaques, isneurotoxic (Science, 250, 279 (1990)). However, various theories havebeen proposed as for the reason why Aβ causes the cell death, and anyauthentic theory has not yet been established. Takashima et al. observedthat the cell death was caused by Aβ treatment of fetal rat hippocampusprimary culture system, and then found that the TPK1 activity wasincreased by Aβ treatment and the cell death by Aβ was inhibited byantisense of TPK1 (Proc. Natl. Acad. Sci. USA, 90, 7789 (1993); JapanesePatent Un-examined Publication [Kokai] No. 6-329551/1994).

In view of the foregoing, compounds which inhibit the TPK1 activity maypossibly suppress the neurotoxicity of Aβ and the formation of PHF andinhibit the nerve cell death in the Alzheimer disease, thereby cease ordefer the progress of the disease. The compounds may also be possiblyused as a medicament for therapeutic treatment of ischemiccerebrovascular disorder, Down syndrome, cerebral amyloid angiopathy,cerebral bleeding due to Lewy body disease and the like by suppressingthe cytotoxicity of Aβ. Furthermore, the compounds may possibly be usedas a medicament for therapeutic treatment of neurodegenerative diseasessuch as progressive supranuclear palsy, subacute sclerosingpanencephalitic parkinsonism, postencephalitic parkinsonism, pugilisticencephalitis, Guam parkinsonism-dementia complex, Lewy body disease,Pick's disease, corticobasal degeneration and frontotemporal dementia.

As structurally similar compounds to the compounds of the presentinvention represented by formula (I) described later, compoundsrepresented by the following formula (A) are known:

wherein R represents 2,6-dichlorobenzyl group,2-(2-chlorophenyl)ethylamino group, 3-phenylpropylamino group, or1-methyl-3-phenylpropylamino group (WO98/24782). The compoundsrepresented by formula (A) are characterized to have 4-fluorophenylgroup at the 5-position of the pyrimidine ring, and not falling withinthe scope of the present invention. Moreover, main pharmacologicalactivity of the compounds represented by formula (A) isanti-inflammatory effect, whereas the compounds of the present inventionrepresented by formula (I) are useful as a TPK1 inhibitor or amedicament for therapeutic treatment of neurodegenerative diseases, andtherefore, their pharmacological activities are totally different toeach other.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide compounds useful as anactive ingredient of a medicament for preventive and/or therapeutictreatment of diseases such as Alzheimer disease and the like. Morespecifically, the object is to provide novel compounds useful as anactive ingredient of a medicament that enables radical prevention and/ortreatment of the diseases such as Alzheimer disease by inhibiting theTPK1 activity to suppress the neurotoxicity of Aβ and the formation ofthe PHF and by inhibiting the drop of nerve cells.

In order to achieve the foregoing object, the inventors of the presentinvention conducted screenings of various compounds having inhibitoryactivity against the phosphorylation of TPK1. As a result, they foundthat compounds represented by the following formula (I) had the desiredactivity and were useful as an active ingredient of a medicament forpreventive and/or therapeutic treatment of the aforementioned diseases.The present invention was achieved on the basis of these findings.

The present invention thus provides pyrimidone derivatives representedby formula (I) or salts thereof, solvates thereof or hydrates thereof:

-   -   wherein R¹ represents a C₁–C₁₈ alkyl group which may be        substituted, a C₃–C₁₈ alkenyl group which may be substituted, a        C₃–C₁₈ alkynyl group which may be substituted, a C₃–C₈        cycloalkyl group which may be substituted, a C₆–C₁₄ aryl group        which may be substituted, a C₁–C₁₈ alkyloxy group which may be        substituted, a C₃–C₁₈ alkenyloxy group which may be substituted,        a C₃–C₁₈ alkynyloxy group which may be substituted, a C₃–C₈        cycloalkyloxy group which may be substituted, a C₆–C₁₄ aryloxy        group which may be substituted, a heterocyclic group which may        be substituted, or a group represented by —N(R⁴)—W—R⁵ wherein R⁴        and R⁵ independently represent a hydrogen atom, a C₁–C₁₈ alkyl        group which may be substituted, a C₃–C₁₈ alkenyl group which may        be substituted, a C₃–C₁₈ alkynyl group which may be substituted,        a C₃–C₈ cycloalkyl group which may be substituted, or a C₆–C₁₄        aryl group which may be substituted, and symbol “W” represents a        single bond, carbonyl group, sulfonyl group, or a nitrogen atom        which may be substituted with a C₁–C₁₈ alkyl group which may be        substituted;    -   R² represents hydrogen atom, hydroxyl group, a C₁–C₈ alkyl group        which may be substituted, a C₃–C₈ alkenyl group which may be        substituted, a C₃–C₈ cycloalkyl group which may be substituted,        a C₁–C₈ alkyloxy group which may be substituted, a C₃–C₈        cycloalkyloxy group which may be substituted, a C₆–C₁₄ aryloxy        group which may be substituted, a C₁–C₈ alkylthio group which        may be substituted, a halogen atom, nitro group, cyano group, an        amino group which may be substituted, carboxyl group, a C₁–C₈        alkyloxycarbonyl group which may be substituted, a C₃–C₈        cycloalkyloxycarbonyl group which may be substituted, carbamoyl        group, a C₁–C₈ alkylaminocarbonyl group which may be        substituted, or a C₁–C₈ dialkylaminocarbonyl group which may be        substituted; and    -   R³ represents a pyridyl group which may be substituted.

According to another aspect of the present invention, there is provideda medicament comprising as an active ingredient a substance selectedfrom the group consisting of the pyrimidone derivatives represented byformula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof. As preferred embodiments ofthe medicament, there are provided the aforementioned medicament whichis used for preventive and/or therapeutic treatment of diseases causedby tau protein kinase 1 hyperactivity, and the aforementioned medicamentwhich is used for preventive and/or therapeutic treatment ofneurodegenerative diseases. As further preferred embodiments of thepresent invention, there are provided the aforementioned medicamentwherein the diseases are selected from the group consisting of Alzheimerdisease, ischemic cerebrovascular accidents, Down syndrome, cerebralbleeding due to cerebral amyloid angiopathy, progressive supranuclearpalsy, subacute sclerosing panencephalitic parkinsonism,postencephalitic parkinsonism, pugilistic encephalitis, Guamparkinsonism-dementia complex, Lewy body disease, Pick's disease,corticobasal degeneration and frontotemporal dementia; and theaforementioned medicament in the form of pharmaceutical compositioncontaining the above substance as an active ingredient together with oneor more pharmaceutical additives. The present invention further providesan inhibitor of tau protein kinase 1 comprising as an active ingredienta substance selected from the group consisting of the pyrimidonederivatives of formula (I) and the salts thereof, and the solvatesthereof and the hydrates thereof.

According to further aspects of the present invention, there areprovided a method for preventive and/or therapeutic treatment ofdiseases caused by tau protein kinase 1 hyperactivity, which comprisesthe step of administering to a patient a preventively and/ortherapeutically effective amount of a substance selected from the groupconsisting of the pyrimidone derivatives of formula (I) and thephysiologically acceptable salts thereof, and the solvates thereof andthe hydrates thereof; and a use of a substance selected from the groupconsisting of the pyrimidone derivatives of formula (I) and thephysiologically acceptable salts thereof, and the solvates thereof andthe hydrates thereof for the manufacture of the aforementionedmedicament.

The present invention is also directed to a method for therapeutictreatment of a disease caused by tau protein kinase 1 hyperactivity,which comprises administering to a patient a therapeutically effectiveamount of a substance selected from the group consisting of a pyrimidonederivative represented by formula (I) or a salt thereof, or a solvatethereof or a hydrate thereof:

wherein

-   -   R¹ represents a group represented by —N(R⁴)—W—R⁵ wherein        -   R⁴ and R⁵ independently represent a hydrogen atom, a C₁–C₁₈            alkyl group which may be substituted, a C₃–C₁₈ alkenyl group            which may be substituted, a C₃–C₁₈ alkynyl group which may            be substituted, a C₃–C₈ cycloalkyl group which may be            substituted, or a C₆–C₁₄ aryl group which may be            substituted, and        -   symbol “W” represents a single bond, a carbonyl group, a            sulfonyl group, or a nitrogen atom which may be substituted            with a C₁–C₁₈ alkyl group which may be substituted;    -   R² represents a hydrogen atom, hydroxyl group, an unsubstituted        C₁–C₈ alkyl group, a C₃–C₈ alkenyl group which may be        substituted, a C₃–C₈ cycloalkyl group which may be substituted,        a C₁–C₈ alkyloxy group which may be substituted, a C₃–C₈        cycloalkyloxy group which may be substituted, a C₆–C₁₄ aryloxy        group which may be substituted, a C₁–C₈ alkylthio group which        may be substituted, a halogen atom, nitro group, cyano group, an        amino group which may be substituted, carboxyl group, a C₁–C₈        alkyloxycarbonyl group which may be substituted, a C₃–C₈        cycloalkyloxycarbonyl group which may be substituted, carbamoyl        group, a C₁–C₈ alkylaminocarbonyl group which may be        substituted, or a C₁–C₈ dialkylaminocarbonyl group which may be        substituted; and    -   R³ represents a pyridyl group which may be substituted.

The present invention is also directed to a method for prophylactictreatment of a disease caused by tau protein kinase 1 hyperactivity,which comprises administering to a patient a prophylactically effectiveamount of a substance selected from the group consisting of a pyrimidonederivative represented by formula (I) or a salt thereof, or a solvatethereof or a hydrate thereof:

wherein

-   -   R¹ represents a group represented by —N(R⁴)—W—R⁵ wherein        -   R⁴ and R⁵ independently represent a hydrogen atom, a C₁–C₁₈            alkyl group which may be substituted, a C₃–C₁₈ alkenyl group            which may be substituted, a C₃–C₁₈ alkynyl group which may            be substituted, a C₃–C₈ cycloalkyl group which may be            substituted, or a C₆–C₁₄ aryl group which may be            substituted, and        -   symbol “W” represents a single bond, a carbonyl group, a            sulfonyl group, or a nitrogen atom which may be substituted            with a C₁–C₁₈ alkyl group which may be substituted;    -   R² represents a hydrogen atom, hydroxyl group, an unsubstituted        C₁–C₈ alkyl group, a C₃–C₈ alkenyl group which may be        substituted, a C₃–C₈ cycloalkyl group which may be substituted,        a C₁–C₈ alkyloxy group which may be substituted, a C₃–C₈        cycloalkyloxy group which may be substituted, a C₆–C₁₄ aryloxy        group which may be substituted, a C₁–C₈ alkylthio group which        may be substituted, a halogen atom, nitro group, cyano group, an        amino group which may be substituted, carboxyl group, a C₁–C₈        alkyloxycarbonyl group which may be substituted, a C₃–C₈        cycloalkyloxycarbonyl group which may be substituted, carbamoyl        group, a C₁–C₈ alkylaminocarbonyl group which may be        substituted, or a C₁–C₈ dialkylaminocarbonyl group which may be        substituted; and    -   R³ represents a pyridyl group which may be substituted.

The present invention is also directed to a method of inhibiting tauprotein kinase 1 which comprises administering to a mammal atherapeutically effective amount of at least one pyrimidone derivativerepresented by formula (I) or a salt thereof, or a solvate thereof or ahydrate thereof

wherein

-   -   R¹ represents a group represented by —N(R⁴)—W—R⁵ wherein        -   R⁴ and R⁵ independently represent a hydrogen atom, a C₁–C₁₈            alkyl group which may be substituted, a C₃–C₁₈ alkenyl group            which may be substituted, a C₃–C₁₈ alkynyl group which may            be substituted, a C₃–C₈ cycloalkyl group which may be            substituted, or a C₆–C₁₄ aryl group which may be            substituted, and        -   symbol “W” represents a single bond, a carbonyl group, a            sulfonyl group, or a nitrogen atom which may be substituted            with a C₁–C₁₈ alkyl group which may be substituted;    -   R² represents a hydrogen atom, hydroxyl group, an unsubstituted        C₁–C₈ alkyl group, a C₃–C₈ alkenyl group which may be        substituted, a C₃–C₈ cycloalkyl group which may be substituted,        a C₁–C₈ alkyloxy group which may be substituted, a C₃–C₈        cycloalkyloxy group which may be substituted, a C₆–C₁₄ aryloxy        group which may be substituted, a C₁–C₈ alkylthio group which        may be substituted, a halogen atom, nitro group, cyano group, an        amino group which may be substituted, carboxyl group, a C₁–C₈        alkyloxycarbonyl group which may be substituted, a C₃–C₈        cycloalkyloxycarbonyl group which may be substituted, carbamoyl        group, a C₁–C₈ alkylaminocarbonyl group which may be        substituted, or a C₁–C₈ dialkylaminocarbonyl group which may be        substituted; and    -   R³ represents a pyridyl group which may be substituted.

The disease can be a neurodegenerative disease.

The disease can be selected from the group consisting of Alzheimerdisease, ischemic cerebrovascular accidents, Down syndrome, cerebralbleeding due to cerebral amyloid angiopathy, progressive supranuclearpalsy, subacute sclerosing panencephalitic parkinsonism,postencephalitic parkinsonism, pugilistic encephalitis, Guamparkinsonism-dementia complex, Lewy body disease, Pick's disease,corticobasal degeneration and frontotemporal dementia.

R² can represent a hydrogen atom and R³ can represent a 4-pyridyl groupwhich may be substituted.

R² can represent an unsubstituted, linear C₁–C₈ alkyl group.

The present invention is also directed to a pyrimidone derivativerepresented by formula (I) or a salt thereof, or a solvate thereof or ahydrate thereof:

wherein

-   -   R¹ represents a group represented by —N(R⁴)—W—R⁵ wherein        -   R⁴ represents a hydrogen atom;        -   R⁵ represents a C₁–C₁₈ alkyl group which may be substituted,            a C₃–C₁₈ alkenyl group which may be substituted, a C₃–C₁₈            alkynyl group which may be substituted, a C₃–C₈ cycloalkyl            group which may be substituted, or a C₆–C₁₄ aryl group which            may be substituted, and        -   symbol “W” represents a single bond, a carbonyl group, a            sulfonyl group, or a nitrogen atom which may be substituted            with a C₁–C₁₈ alkyl group which may be substituted;    -   R² represents a hydrogen atom, hydroxyl group, an unsubstituted,        linear C₁–C₈ alkyl group, a C₃–C₈ alkenyl group which may be        substituted, a C₃–C₈ cycloalkyl group which may be substituted,        a C₁–C₈ alkyloxy group which may be substituted, a C₃–C₈        cycloalkyloxy group which may be substituted, a C₆–C₁₄ aryloxy        group which may be substituted, a C₁–C₈ alkylthio group which        may be substituted, a halogen atom, nitro group, cyano group, an        amino group which may be substituted, carboxyl group, a C₁–C₈        alkyloxycarbonyl group which may be substituted, a C₃–C₈        cycloalkyloxycarbonyl group which may be substituted, carbamoyl        group, a C₁–C₈ alkylaminocarbonyl group which may be        substituted, or a C₁–C₈ dialkylaminocarbonyl group which may be        substituted; and    -   R³ represents a 4-pyridyl group which may be substituted.

The present invention is also directed to a pyrimidone derivativerepresented by formula (I) or a salt thereof, or a solvate thereof or ahydrate thereof:

-   -   wherein R¹ represents a group represented by —N(R⁴)—W—R⁵ wherein        -   R⁴ represents a hydrogen atom, a C₁–C₁₈ alkyl group which            may be substituted, a C₃–C₁₈ alkenyl group which may be            substituted, a C₃–C₁₈ alkynyl group which may be            substituted, a C₃–C₈ cycloalkyl group which may be            substituted, or a C₆–C₁₄ aryl group which may be            substituted,        -   R⁵ represents an alkyl group which may be substituted, said            alkyl group being one of ethyl group, n-propyl group,            isopropyl group, n-butyl group, isobutyl group, sec-butyl            group, tert-butyl group, n-pentyl group, isopentyl group,            neopentyl group, 1,1-dimethylpropyl group, n-hexyl group,            isohexyl group, a linear or branched heptyl group, octyl            group, nonyl group, decyl group, undecyl group, dodecyl            group, tridecyl group, tetradecyl group, pentadecyl group or            octadecyl group, a C₃–C₁₈ alkenyl group which may be            substituted, a C₃–C₁₈ alkynyl group which may be            substituted, a C₃–C₈ cycloalkyl group which may be            substituted, or a C₆–C₁₄ aryl group which may be            substituted, and        -   symbol “W” represents a single bond, a carbonyl group, a            sulfonyl group, or a nitrogen atom which may be substituted            with a C₁–C₁₈ alkyl group which may be substituted;    -   R² represents a hydrogen atom, hydroxyl group, an unsubstituted,        linear C₁–C₈ alkyl group, a C₃–C₈ alkenyl group which may be        substituted, a C₃–C₈ cycloalkyl group which may be substituted,        a C₁–C₈ alkyloxy group which may be substituted, a C₃–C₈        cycloalkyloxy group which may be substituted, a C₆–C₁₄ aryloxy        group which may be substituted, a C₁–C₈ alkylthio group which        may be substituted, a halogen atom, nitro group, cyano group, an        amino group which may be substituted, carboxyl group, a C₁–C₈        alkyloxycarbonyl group which may be substituted, a C₃–C₈        cycloalkyloxycarbonyl group which may be substituted, carbamoyl        group, a C₁–C₈ alkylaminocarbonyl group which may be        substituted, or a C₁–C₈ dialkylaminocarbonyl group which may be        substituted; and    -   R³ represents a 4-pyridyl group which may be substituted.

R⁵ can represent a C₁–C₁₈ alkyl group substituted with a C₆–C₁₀ aryl.

R² can represent a hydrogen atom, an unsubstituted, linear C₁–C₈ alkylgroup, or a halogen atom.

R² can represent a hydrogen atom.

The symbol “W” can represent a single bond or a carbonyl group.

R¹ can represent N,N-diethylamino group, N,N-dipropylamino group,N-benzyl-N-methylamino group, N-isobutyl-N-methylamino group,N-benzylamino group, N-(3-hydroxypropyl)amino group,N-cyclohexylmethylamino group, N-phenylamino group,N-(4-ethylphenyl)amino group, N-(3-bromophenyl)amino group orN-(3-methoxyphenyl)amino group.

R³ can represent 4-pyridyl group.

The pyrimidone derivative can be selected from the group of:

-   2-(N-phenylamino)-6-(4-pyridyl)pyrimidin-4-one,-   2-(N,N-diethylamino)-6-(4-pyridyl)pyrimidin-4-one,-   2-(N,N-dipropylamino)-6-(4-pyridyl)pyrimidin-4-one,-   2-(N-benzylamino)-6-(4-pyridyl)pyrimidin-4-one,-   2-(N-benzyl-N-methylamino)-6-(4-pyridyl)pyrimidin-4-one,-   2-(N-(3-bromophenyl)amino)-6-(4-pyridyl)pyrimidin-4-one,-   2-(N-(4-ethylphenyl)amino)-6-(4-pyridyl)pyrimidin-4-one,-   2-(N-(3-methoxyphenyl)amino)-6-(4-pyridyl)pyrimidin-4-one,-   2-(N-cyclohexylmethylamino)-6-(4-pyridyl)pyrimidin-4-one, and-   2-(N-isobutyl-N-methylamino)-6-(4-pyridyl)pyrimidin-4-one,    or a salt thereof, or a solvate thereof or a hydrate thereof.

The present invention is also directed to a pharmaceutical compositioncomprising as an active ingredient a substance selected from the groupconsisting of the pyrimidone derivatives or a salt thereof, or a solvatethereof or a hydrate thereof according to any of the above.

BEST MODE FOR CARRYING OUT THE INVENTION

The “alkyl group” or an alkyl portion of a functional group containingthe alkyl portion (alkoxyl group, for example) used herein may be eitherlinear or branched. The C₁–C₁₈ alkyl group represented by R¹ may be, forexample, methyl group, ethyl group, n-propyl group, isopropyl group,n-butyl group, isobutyl group, sec-butyl group, tert-butyl group,n-pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropylgroup, n-hexyl group, isohexyl group, or a linear or branched heptylgroup, octyl group, nonyl group, decyl group, undecyl group, dodecylgroup, tridecyl group, tetradecyl group, pentadecyl group or octadecylgroup. In the specification, when a functional group is defined as“which may be substituted” or “optionally substituted”, the number ofsubstituents as well as their types and substituting positions are notparticularly limited, and when two or more substituents are present,they may be the same or different.

When the C₁–C₁₈ alkyl group represented by R¹ has one or moresubstituents A, the alkyl group may have one or more substituents Aselected form the group consisting of a C₃–C₈ cycloalkyl group such ascyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexylgroup, cycloheptyl group, and cyclooctyl group; a C₆–C₁₀ aryl group suchas phenyl group, 1-naphthyl group, and 2-naphthyl group; a C₃–C₈cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group,cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, andcyclooctyloxy group; fluorenyl group; a C₁–C₅ alkoxyl group such asmethoxy group, ethoxy group, propoxy group, isopropoxy group, butoxygroup, isobutoxy group, tert-butoxy group, pentyloxy group, andisopentyloxy group; a C₆–C₁₄ aryloxy group such as phenoxy group, andnaphthoxy group; a C₁–C₅ alkylthio group such as methylthio group,ethylthio group, propylthio group, butylthio group, and pentylthiogroup; a C₆–C₁₄ arylthio group such as phenylthio group, andnaphthylthio group; a C₁–C₅ alkylsulfonyl group such as methanesulfonylgroup, ethanesulfonyl group, propanesulfonyl group, butanesulfonylgroup, and pentanesulfonyl group; a C₆–C₁₄ arylsulfonyl group such asphenylsulfonyl group, and naphthylsulfonyl group; a halogen atom such asfluorine atom, chlorine atom, bromine atom, and iodine atom; a C₁–C₅halogenated alkyl group such as trifluoromethyl group; hydroxyl group;nitro group; oxo group; formyl group; a C₂–C₆ alkylcarbonyl group suchas acetyl group, propionyl group, butyryl group, and valeryl group;amino group; a C₁–C₅ monoalkylamino group such as methylamino group,ethylamino group, propylamino group, isopropylamino group, butylaminogroup, isobutylamino group, tert-butylamino group, pentylamino group,and isopentylamino group; a C₂–C₁₀ dialkylamino group such asdimethylamino group, ethylmethylamino group, diethylamino group,methylpropylamino group, and diisopropylamino group; and a residue ofheterocyclic ring having 1–4 hetero atoms selected from oxygen atom,sulfur atom, and nitrogen atom, and having total ring-constituting atomsof 5–10, for example, furan ring, dihydrofuran ring, tetrahydrofuranring, pyran ring, dihydropyran ring, tetrahydropyran ring, benzofuranring, isobenzofuran ring, chromene ring, chroman ring, isochroman ring,thiophene ring, benzothiophene ring, pyrrole ring, pyrroline ring,pyrrolidine ring, imidazole ring, imidazoline ring, imidazolidine ring,pyrazole ring, pyrazoline ring, pyrazolidine ring, triazole ring,tetrazole ring, pyridine ring, pyridine oxide ring, piperidine ring,pyrazine ring, piperazine ring, pyrimidine ring, pyridazine ring,indolizine ring, indole ring, indoline ring, isoindole ring, isoindolinering, indazole ring, benzimidazole ring, purine ring, quinolizine ring,quinoline ring, phthalazine ring, naphtylidine ring, quinoxaline ring,quinazoline ring, cinnoline ring, pteridine ring, oxazole ring,oxazolidine ring, isoxazole ring, isoxazolidine ring, thiazole ring,benzothiazole ring, thiazylidine ring, isothiazole ring, isothiazolidinering, dioxane ring, dithian ring, morpholine ring, thiomorpholine ring,phthalimide ring and the like.

When an aryl group or a heterocyclic group is present as a substituent,the group may have one or more substituents B selected form the groupconsisting of a C₁–C₁₈ alkyl group such as methyl group, ethyl group,propyl group, isopropyl group, butyl group, isobutyl group, sec-butylgroup, tert-butyl group, pentyl group, isopentyl group, neopentyl group,1,1-dimethylpropyl group, hexyl group, isohexyl group, heptyl group,octyl group, nonyl group, decyl group, undecyl group, dodecyl group,tridecyl group, tetradecyl group, pentadecyl group, and octadecyl group,and the aforementioned substituent A.

Examples of the C₃–C₁₈ alkenyl group represented by R¹ include, forexample, allyl group, 2-butenyl group, 3-butenyl group, 2-pentenylgroup, 3-pentenyl group, 4-pentenyl group, 2-methyl-2-butenyl group,3-methyl-2-butenyl group, 2-hexenyl group, 5-hexenyl group, 2-heptenylgroup, 6-heptenyl group, 2-octenyl group, 7-octenyl group, 2-nonenylgroup, 8-nonenyl group and the like, and examples of the C₃–C₁₈ alkynylgroup represented by R¹ include, for example, propargyl group, 2-butynylgroup, 3-butynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynylgroup, 1-methyl-2-pentynyl group, 4-methyl-2-pentynyl group, 2-hexynylgroup, 5-hexynyl group, 2-heptynyl group, 6-heptynyl group, 2-octynylgroup, 7-octynyl group and the like. These groups may be substitutedwith one or more substituents A.

Examples of the C₃–C₈ cycloalkyl group represented by R¹ include, forexample, cyclopropyl group, cyclobutyl group, cyclopentyl group,cyclohexyl group, cycloheptyl group, cyclooctyl group and the like, andexamples of the C₆–C₁₄ aryl group represented by R¹ include, forexample, phenyl group, naphthyl group, anthryl group and the like. Thesegroups may be substituted with one or more substituents B. The C₆–C₁₄aryl group represented by R¹ may further have one or more substituentsselected from the group consisting of a hydroxyalkyl group such ashydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, and3-hydroxypropyl group; a C₁–C₃ alkyl group having a C₁–C₆alkylcarbonyloxy group such as formyloxymethyl group, acetoxymethylgroup, 1-acetoxyethyl group, 2-acetoxyethyl group, 3-acetoxypropylgroup, propionyloxymethyl group, butyryloxymethyl group, andvaleryloxymethyl group; a C₁–C₃ aminoalkyl group such as aminomethylgroup, 1-aminoethyl group, 2-aminoethyl group, and 3-aminopropyl group;a monoalkylamino(C₁–C₃ alkyl) group having a C₁–C₈ alkyl group on thenitrogen atom such as methylaminomethyl group, ethylaminomethyl group,1-methylaminoethyl group, 2-methylaminoethyl group, and3-methylaminopropyl group; and a dialkylamino(C₁–C₃ alkyl) group havingthe same or different C₁–C₈ alkyl groups on the nitrogen atom such asdimethylaminomethyl group, diethylaminomethyl group,1-dimethylaminoethyl group, 2-dimethylaminoethyl group, and3-dimethylaminopropyl group.

Examples of the C₁–C₁₈ alkyloxy group represented by R¹ include, forexample, methoxy group, ethoxy group, propoxy group, isopropoxy group,butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group,pentyloxy group, isopentyloxy group, neopentyloxy group,1,1-dimethylpropyloxy group, hexyloxy group, isohexyloxy group,heptyloxy group, octyloxy group, nonyloxy group, decyloxy group,undecyloxy group, dodecyloxy group, tridecyloxy group, tetradecyloxygroup, pentadecyloxy group, octadecyloxy group and the like. Examples ofthe C₃–C₁₈ alkenyloxy group represented by R¹ include, for example,allyloxy group, 2-butenyloxy group, 3-butenyloxy group, 2-pentenyloxygroup, 3-pentenyloxy group, 4-pentenyloxy group, 2-methyl-2-butenyloxygroup, 3-methyl-2-butenyloxy group, 2-hexenyloxy group, 5-hexenyloxygroup, 2-heptenyloxy group, 6-heptenyloxy group, 2-octenyloxy group,7-octenyloxy group, 2-nonenyloxy group, 8-nonenyloxy group and the like.Examples of the C₃–C₁₈ alkynyloxy group represented by R¹ include, forexample, propargyloxy group, 2-butynyloxy group, 3-butynyloxy group,2-pentynyloxy group, 3-pentynyloxy group, 4-pentynyloxy group,1-methyl-2-pentynyloxy group, 4-methyl-2-pentynyloxy group, 2-hexynyloxygroup, 5-hexynyloxy group, 2-heptynyloxy group, 6-heptynyloxy group,2-octynyloxy group, 7-octynyloxy group and the like. These groups may besubstituted with one or more substituents A.

Examples of the C₃–C₈ cycloalkyloxy group represented by R¹ include, forexample, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxygroup, cyclohexyloxy group, cycloheptyloxy group, and cyclooctyloxygroup, and examples of the C₆–C₁₄ aryloxy group represented by R¹include, for example, phenoxy group, naphthoxy group, and anthryloxygroup. These groups may be substituted with one or more substituents B.

Examples of the heterocyclic group represented by R¹ include, forexample, residues of heterocyclic rings having 1–4 hetero atoms selectedfrom oxygen atom, sulfur atom, and nitrogen atom, and having totalring-constituting atoms of 5–10, for example, furan ring, dihydrofuranring, tetrahydrofuran ring, pyran ring, dihydropyran ring,tetrahydropyran ring, benzofuran ring, isobenzofuran ring, chromenering, chroman ring, isochroman ring, thiophene ring, benzothiophenering, pyrrole ring, pyrroline ring, pyrrolidine ring, imidazole ring,imidazoline ring, imidazolidine ring, pyrazole ring, pyrazoline ring,pyrazolidine ring, triazole ring, tetrazole ring, pyridine ring,pyridine oxide ring, piperidine ring, pyrazine ring, piperazine ring,pyrimidine ring, pyridazine ring, indolizine ring, indole ring, indolinering, isoindole ring, isoindoline ring, indazole ring, benzimidazolering, purine ring, quinolizine ring, quinoline ring, phthalazine ring,naphtylidine ring, quinoxaline ring, quinazoline ring, cinnoline ring,pteridine ring, oxazole ring, oxazolidine ring, isoxazole ring,isoxazolidine ring, thiazole ring, benzothiazole ring, thiazylidinering, isothiazole ring, isothiazolidine ring, dioxane ring, dithianring, morpholine ring, thiomorpholine ring, phthalimide ring and thelike. The heterocyclic group may have one or more substituents B.

As the optionally substituted C₁–C₁₈ alkyl group, and as the optionallysubstituted C₃–C₁₈ alkenyl group, the optionally substituted C₃–C₁₈alkynyl group, the optionally substituted C₃–C₈ cycloalkyl group, andthe optionally substituted C₆–C₁₄ aryl group which are independentlyrepresented by R⁴ and R⁵, such as those explained as to R¹ may be used.When the symbol “W” represents nitrogen atom, as the optionallysubstituted C₁–C₁₈ alkyl that may be present on the nitrogen atom, suchas those explained as to R¹ may be used.

Examples of the C₁–C₈ alkyl group represented by R² include, forexample, methyl group, ethyl group, n-propyl group, isopropyl group,n-butyl group, isobutyl group, sec-butyl group, tert-butyl group,n-pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropylgroup, n-hexyl group, isohexyl group, n-heptyl group, n-octyl group andthe like, and examples of the C₃–C₈ alkenyl group represented by R²include, for example, allyl group, 2-butenyl group, 3-butenyl group,2pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-methyl-2-butenylgroup, 3-methyl-2-butenyl group, 2-hexenyl group, 5-hexenyl group,2-heptenyl group, 6-heptenyl group, 2-octenyl group, 7-octenyl group andthe like. These groups may be have one or more substituents A.

Examples of the C₁–C₈alkyloxy group represented by R² include, forexample, methoxy group, ethoxy group, propoxy group, isopropoxy group,butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group,pentyloxy group, isopentyloxy group, neopentyloxy group,1,1-dimethylpropyloxy group, hexyloxy group, isohexyloxy group,heptyloxy group, octyloxy group and the like. Examples of the C₁–C₈alkylthio group represented by R² include, for example, methylthiogroup, ethylthio group, propylthio group, isopropylthio group, butylthiogroup, isobutylthio group, sec-butylthio group, tert-butylthio group,pentylthio group, isopentylthio group, neopentyl thio group,1,1-dimethylpropylthio group, hexylthio group, isohexylthio group,heptylthio group, octylthio group and the like. These groups may be haveone or more substituents A.

Examples of the C₁–C₈ alkyloxycarbonyl group represented by R² include,for example, methoxycarbonyl group, ethoxycarbonyl group,propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group,isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonylgroup, pentyloxycarbonyl group, isopentyloxycarbonyl group,neopentyloxycarbonyl group, 1,1-dimethylpropyloxycarbonyl group,hexyloxycarbonyl group, isohexyloxycarbonyl group, heptyloxycarbonylgroup, octyloxycarbonyl group and the like, and examples of the C₃–C₈cycloalkyloxycarbonyl group represented by R² include, for example,cyclopropyloxycarbonyl group, cyclobutyloxycarbonyl group,cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group,cycloheptyloxycarbonyl group, cyclooctyloxy carbonyl group and the like.The aforementioned cycloalkyloxycarbonyl groups may have one or moresubstituents B, and the aforementioned alkyloxycarbonyl groups may haveone or more substituents A.

Examples of the C₁–C₈ alkylaminocarbonyl group represented by R²include, for example, methylaminocarbonyl group, ethylaminocarbonylgroup, propylaminocarbonyl group, isopropylaminocarbonyl group,butylaminocarbonyl group, isobutylaminocarbonyl group,sec-butylaminocarbonyl group, tert-butylaminocarbonyl group,pentylaminocarbonyl group, isopentylaminocarbonyl group,neopentylaminocarbonyl group, 1,1dimethylpropylaminocarbonyl group,hexylaminocarbonyl group, isohexylaminocarbonyl group,heptylaminocarbonyl group, octylaminocarbonyl group and the like.Examples of the C₁–C₈ dialkylaminocarbonyl group represented by R²include, for example, dimethylaminocarbonyl group, diethylaminocarbonylgroup, dipropylaminocarbonyl group, diisopropylaminocarbonyl group,dibutylaminocarbonyl group, diisobutylaminocarbonyl group,dipentylaminocarbonyl group, diisopentylaminocarbonyl group,dihexylaminocarbonyl group, diisohexylaminocarbonyl group,diheptylaminocarbonyl group, dioctylaminocarbonyl group and the like.These groups may have one or more substituents A.

As the optionally substituted C₃–C₈ cycloalkyl group, optionallysubstituted C₃–C₈ cycloalkyloxy group, and optionally substituted C₆–C₁₄aryloxy group represented by R², such as those explained as to R¹ may beused. R³ represents a pyridyl group, which may be any one of 2-pyridylgroup, 3-pyridyl group, and 4-pyridyl group. The pyridyl group may haveone or more substituents B.

R¹ may preferably a C₁–C₁₈ alkyl group which may be substituted, aC₃–C₁₈ alkenyl group which may be substituted, a C₃–C₁₈ alkynyl groupwhich may be substituted, a C₃–C₈ cycloalkyl group which may besubstituted, a C₆–C₁₄ aryl group which may be substituted, aheterocyclic group which may be substituted by an alkyl group, or agroup represented by —N(R⁴)—W—R⁵ wherein R⁴ and R⁵ independentlyrepresent a hydrogen atom, a C₁–C₁₈ alkyl group which may besubstituted, a C₃–C₁₈ alkenyl group which may be substituted, a C₃–C₁₈alkynyl group which may be substituted, a C₃–C₈ cycloalkyl group whichmay be substituted, or a C₆–C₁₄ aryl group which may be substituted, andsymbol “W” represents a single bond, carbonyl group, sulfonyl group, ora nitrogen atom which may be substituted with a C₁–C₁₈ alkyl group whichmay be substituted.

More preferably, R¹ may be a C₁–C₁₈ alkyl group which may besubstituted, a C₃–C₈ cycloalkyl group which may be substituted, a C₆–C₁₄aryl group which may be substituted, a heterocyclic group which may besubstituted by an unsubstituted alkyl group, or a group represented by—N(R⁴)—W—R⁵ wherein R⁴ and R⁵ independently represent a hydrogen atom, aC₁–C₁₈ alkyl group, or a substituted C₆–C₁₄ aryl group which may besubstituted, and symbol “W” represents a single bond.

R² may preferably be hydrogen atom, a C₁–C₈ alkyl group which may besubstituted, a C₃–C₈ alkenyl group which may be substituted, a C₃–C₈cycloalkyl group which may be substituted, a halogen atom, nitro group,cyano group, an amino group which may be substituted, carboxyl group, aC₁–C₈ alkyloxycarbonyl group which may be substituted, a C₃–C₈cycloalkyloxycarbonyl group which may be substituted, carbamoyl group, aC₁–C₈ alkylaminocarbonyl group which may be substituted, or a C₁–C₈dialkylaminocarbonyl group which may be substituted, and morepreferably, hydrogen atom, a C₁–C₈ alkyl group, or a halogen atom, andmost preferably hydrogen atom. R³ may preferably be 3-pyridyl group or4-pyridyl group, and more preferably 4-pyridyl group.

The compounds represented by the aforementioned formula (I) may form asalt. Examples of the salt include, when an acidic group exists, saltsof alkali metals and alkaline earth metals such as lithium, sodium,potassium, magnesium, and calcium; salts of ammonia and amines such asmethylamine, dimethylamine, trimethylamine, dicyclohexylamine,tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine,2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, andL-glucamine; or salts with basic amino acids such as lysine,δ-hydroxylysine, and arginine. When a basic group exists, examplesinclude salts with mineral acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid; salts with organicacids such as methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, acetic acid, propionic acid, tartaric acid,fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid,citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid,glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, andsalicylic acid; or salts with acidic amino acids such as aspartic acid,and glutamic acid.

In addition to the pyrimidone derivatives represented by theaforementioned formula (I) and salts thereof, their solvates andhydrates also fall within the scope of the present invention. Thepyrimidone derivatives represented by the aforementioned formula (I) mayhave one or more asymmetric carbon atoms. As for the stereochemistry ofsuch asymmetric carbon atoms, they may independently be in either (R)and (S) configuration, and the pyrimidone derivatives may exist asstereoisomers such as optical isomers, or diastereoisomers. Anystereoisomers of pure form, any mixtures of stereoisomers, racemates andthe like fall within the scope of the present invention. Furthermore, asthe pyrimidone derivatives represented by the aforementioned formula(I), a 3H-4-one compound, a 4-hydroxy compound, and a 1H-4-one compoundof may exist as tautomers. The existence of such tautomers is readilyapparent to those skilled in the art, and these tautomers fall withinthe scope of the present invention.

Examples of preferred compounds of the present invention are shown inthe tables below. However, the scope of the present invention is notlimited by the following compounds.

TABLE 1

Compound No. R¹ R² R³  1 Me H 4-Py  2 Et H 4-Py  3 n-Pr H 4-Py  4 i-Pr H4-Py  5 n-Bu H 4-Py  6 i-Bu H 4-Py  7 sec-Bu H 4-Py  8 tert-Bu H 4-Py  9n-C₅H₁₁ H 4-Py  10

H 4-Py  11

H 4-Py  12

H 4-Py  13

H 4-Py  14 n-C₆H₁₃ H 4-Py  15

H 4-Py  16 n-C₇H₁₅ H 4-Py  17 n-C₈H₁₇ H 4-Py  18 n-C₉H₁₉ H 4-Py  19n-C₁₀H₂₁ H 4-Py  20 n-C₁₁H₂₃ H 4-Py  21 n-C₁₂H₂₅ H 4-Py  22 n-C₁₃H₂₇ H4-Py  23 n-C₁₄H₂₉ H 4-Py  24 n-C₁₅H₃₁ H 4-Py  25 n-C₁₆H₃₃ H 4-Py  26n-C₁₇H₃₅ H 4-Py  27 n-C₁₈H₃₇ H 4-Py  28

H 4-Py  29

H 4-Py  30

H 4-Py  31

H 4-Py  32

H 4-Py  33

H 4-Py  34

H 4-Py  35 Ph H 4-Py  36

H 4-Py  37

H 4-Py  38 2-Me—Ph H 4-Py  39 3-Me—Ph H 4-Py  40 4-Me—Ph H 4-Py  412-Et—Ph H 4-Py  42 3-Et—Ph H 4-Py  43 4-Et—Ph H 4-Py  44 2-F—Ph H 4-Py 45 3-F—Ph H 4-Py  46 4-F—Ph H 4-Py  47 2-Cl—Ph H 4-Py  48 3-Cl—Ph H4-Py  49 4-Cl—Ph H 4-Py  50 2-Br—Ph H 4-Py  51 3-Br—Ph H 4-Py  524-Br—Ph H 4-Py  53 2-MeO—Ph H 4-Py  54 3-MeO—Ph H 4-Py  55 4-MeO—Ph H4-Py  56 2-EtO—Ph H 4-Py  57 3-EtO—Ph H 4-Py  58 4-EtO—Ph H 4-Py  592-CN—Ph H 4-Py  60 3-CN—Ph H 4-Py  61 4-CN—Ph H 4-Py  62 2-NO₂—Ph H 4-Py 63 3-NO₂—Ph H 4-Py  64 4-NO₂—Ph H 4-Py  65 2-CF₃—Ph H 4-Py  66 3-CF₃—PhH 4-Py  67 4-CF₃—Ph H 4-Py  68

H 4-Py  69

H 4-Py  70

H 4-Py  71

H 4-Py  72

H 4-Py  73

H 4-Py  74

H 4-Py  75

H 4-Py  76

H 4-Py  77

H 4-Py  78

H 4-Py  79

H 4-Py  80

H 4-Py  81

H 4-Py  82

H 4-Py  83

H 4-Py  84

H 4-Py  85

H 4-Py  86

H 4-Py  87

H 4-Py  88

H 4-Py  89

H 4-Py  90

H 4-Py  91

H 4-Py  92

H 4-Py  93

H 4-Py  94

H 4-Py  95

H 4-Py  96

H 4-Py  97

H 4-Py  98

H 4-Py  99

H 4-Py 100

H 4-Py 101

H 4-Py 102

H 4-Py 103

H 4-Py 104

H 4-Py 105

H 4-Py 106

H 4-Py 107

H 4-Py 108

H 4-Py 109

H 4-Py 110

H 4-Py 111

H 4-Py 112

H 4-Py 113

H 4-Py 114

H 4-Py 115

H 4-Py 116

H 4-Py 117

H 4-Py 118

H 4-Py 119

H 4-Py 120

H 4-Py 121

H 4-Py 122

H 4-Py 123

H 4-Py 124

H 4-Py 125

H 4-Py 126

H 4-Py 127

H 4-Py 128

H 4-Py 129

H 4-Py 130

H 4-Py 131

H 4-Py 132

H 4-Py 133

H 4-Py 134

H 4-Py 135

H 4-Py 136

H 4-Py 137

H 4-Py 138

H 4-Py 139

H 4-Py 140

H 4-Py 141

H 4-Py 142

H 4-Py 143

H 4-Py 144

H 4-Py 145

H 4-Py 146

H 4-Py 147

H 4-Py 148

H 4-Py 149

H 4-Py 150

H 4-Py 151

H 4-Py 152

H 4-Py 153

H 4-Py 154

H 4-Py 155

H 4-Py 156

H 4-Py 157 NH₂ H 4-Py 158 NHMe H 4-Py 159 NHEt H 4-Py 160 NHn-Pr H 4-Py161 NHi-Pr H 4-Py 162 NHn-Bu H 4-Py 163 NHi-Bu H 4-Py 164 NHt-Bu H 4-Py165 NHn-C₅H₁₁ H 4-Py 166 NHn-C₆H₁₃ H 4-Py 167

H 4-Py 168 NHPh H 4-Py 169 NMe₂ H 4-Py 170 NEt₂ H 4-Py 171 Nn-Pr₂ H 4-Py172 NHNH₂ H 4-Py 173 NHNHMe H 4-Py 174 NHNMe₂ H 4-Py 175 NMeNH₂ H 4-Py176 NMeNMe₂ H 4-Py 177 NHCOCH₃ H 4-Py 178 NHCOC₂H₅ H 4-Py 179 NHCOPh H4-Py 180 NHSO₂Me H 4-Py 181 NHSO₂Ph H 4-Py 182

H 4-Py 183 Ph Me 4-Py 184

Me 4-Py 185 Ph Et 4-Py 186

Et 4-Py 187 Ph n-Pr 4-Py 188

n-Pr 4-Py 189 Ph i-Pr 4-Py 190

i-Pr 4-Py 191 Ph n-Bu 4-Py 192

n-Bu 4-Py 193 Ph i-Bu 4-Py 194

i-Bu 4-Py 195 Ph tBu 4-Py 196

tBu 4-Py 197 Ph n-C₅H₁₁ 4-Py 198

n-C₅H₁₁ 4-Py 199 Ph n-C₆H₁₃ 4-Py 200

n-C₆H₁₃ 4-Py 201 Ph

4-Py 202

4-Py 203 Ph

4-Py 204

4-Py 205 Ph

4-Py 206

4-Py 207 Ph

4-Py 208

4-Py 209

4-Py 210

4-Py 211 Me

4-Py 212 Ph

4-Py 213

4-Py 214 Ph

4-Py 215

4-Py 216 Ph

4-Py 217

4-Py 218 Ph OH 4-Py 219

OH 4-Py 220 Ph OMe 4-Py 221

OMe 4-Py 222 Ph OEt 4-Py 223

OEt 4-Py 224 Ph OPh 4-Py 225

OPh 4-Py 226 Ph SMe 4-Py 227

SMe 4-Py 228 Ph F 4-Py 229

F 4-Py 230 Ph Cl 4-Py 231

Cl 4-Py 232 NH₂ Cl 4-Py 233 Ph Br 4-Py 234

Br 4-Py 235 Ph NO₂ 4-Py 236

NO₂ 4-Py 237 Ph CN 4-Py 238

CN 4-Py 239 Ph NH₂ 4-Py 240

NH₂ 4-Py 241 Ph NMe₂ 4-Py 242

NMe₂ 4-Py 243 Ph —COOH 4-Py 244

—COOH 4-Py 245 Ph —COOMe 4-Py 246

—COOMe 4-Py 247 Ph —COOEt 4-Py 248

—COOEt 4-Py 249 Ph CONH₂ 4-Py 250

CONH₂ 4-Py 251 Ph CONMe₂ 4-Py 252

CONMe₂ 4-Py 253 254 Ph 

H H

255 256 Ph 

H H

257 258 Ph 

H H

259 260 Ph 

H H

261 262 Ph 

H H

263 264 Ph 

H H

265 266 Ph 

H H

267 268    269 Ph 

 4-Py H H    H

270 271 Ph 

H H

272 273 Ph 

H H

274 275 Ph 

H H

276 277 Ph 

H H

278 279 Ph 

H H

280 281 Ph 

H H

282 283    284 Ph 

 4-Py H H    H

285 286 Ph 

H H

287 288 Ph 

H H

289 290 Ph 

H H

291 292 Ph 

H H

293 294 Ph 

H H

295 296 Ph 

H H

297298 299 MePh 

HH H

300 4-Py H 301 NMe₂ H 302 303 Ph 

H H

304 305 Ph 

H H

306 307 Ph 

H H

308 309 Ph 

H H

310 311 Ph 

H H

312 313 Ph 

H H

314 315 Ph 

H H

316 317 Ph 

H H

318 319 Ph 

H H

320 321 Ph 

H H

322 323 Ph 

H H

324 325 Ph 

H H

326 327 Ph 

H H

328 329 Ph 

H H

330 331 Ph 

H H

332 333 Ph 

H H

334 335 Ph 

H H

336 337 Ph 

H H

338 339 Ph 

H H

340 341 Ph 

H H

342 343 Ph 

H H

344 345 Ph 

H H

346 347 Ph 

H H

348 349 Ph 

H H

350 351 Ph 

H H

352 2-n-Pr—Ph H 4-Py 353 2-i-Pr—Ph H 4-Py 354 2-n-Bu—Ph H 4-Py 3552-i-Bu—Ph H 4-Py 356 2-sec-Bu—Ph H 4-Py 357 2-tert-Bu—Ph H 4-Py 3582-n-C₅H₁₁—Ph H 4-Py 359 2-n-C₆H₁₃—Ph H 4-Py 360 2-Ph—Ph H 4-Py 3613-n-Pr—Ph H 4-Py 362 3-i-Pr—Ph H 4-Py 363 3-n-Bu—Ph H 4-Py 364 3-i-Bu—PhH 4-Py 365 3-sec-Bu—Ph H 4-Py 366 3-tert-Bu—Ph H 4-Py 367 3-n-C₅H₁₁—Ph H4-Py 368 3-n-C₆H₁₃—Ph H 4-Py 369 3-Ph—Ph H 4-Py 370

H 4-Py 371

H 4-Py 372

H 4-Py 373

H 4-Py 374

H 4-Py 375

H 4-Py 376

H 4-Py 377

H 4-Py 378

H 4-Py 379

H 4-Py 380

H 4-Py 381

H 4-Py 382

H 4-Py 383

H 4-Py 384

H 4-Py 385

H 4-Py 386

H 4-Py 387

H 4-Py 388

H 4-Py 389

H 4-Py 390

H 4-Py 391

H 4-Py 392

H 4-Py 393

H 4-Py 394

H 4-Py 395

H 4-Py 396

H 4-Py 397

H 4-Py 398

H 4-Py 399

H 4-Py 400

H 4-Py 401

H 4-Py 402

H 4-Py 403

H 4-Py 404

H 4-Py 405

H 4-Py 406

H 4-Py 407

H 4-Py 408

H 4-Py 409

H 4-Py 410

H 4-Py 411

H 4-Py 412

H 4-Py 413

H 4-Py 414

H 4-Py 415

H 4-Py 416

H 4-Py 417

H 4-Py 418

H 4-Py 419

H 4-Py 420

H 4-Py 421

H 4-Py 422

H 4-Py 423

H 4-Py 424

H 4-Py 425

H 4-Py 426

H 4-Py 427

H 4-Py 428

H 4-Py 429

H 4-Py 430

H 4-Py 431

H 4-Py 432

H 4-Py 433

H 4-Py 434

H 4-Py 435

H 4-Py 436

H 4-Py 437

H 4-Py 438

H 4-Py 439

H 4-Py 440

H 4-Py 441

H 4-Py

Particularly preferred compounds of the present invention represented byformula (I) include:

-   -   (1) compounds wherein R² is hydrogen atom, a C₁–C₈ alkyl group        which may be substituted, a C₃–C₈ alkenyl group which may be        substituted, a C₃–C₈ cycloalkyl group which may be substituted,        a halogen atom, nitro group, cyano group, an amino group which        may be substituted, carboxyl group, a C₁–C₈ alkyloxycarbonyl        group which may be substituted, a C₃–C₈ cycloalkyloxycarbonyl        group which may be substituted, carbamoyl group, a C₁–C₈        alkylaminocarbonyl group which may be substituted, or a C₁–C₈        dialkylaminocarbonyl group which may be substituted;    -   (2) compounds wherein R¹ is a C₁–C₁₈ alkyl group which may be        substituted, a C₃–C₁₈ alkenyl group which may be substituted, a        C₃–C₁₈ alkynyl group which may be substituted, a C₃–C₈        cycloalkyl group which may be substituted, a C₆–C₁₄ aryl group        which may be substituted, a heterocyclic group which may be        substituted by an alkyl group, or a group represented by        —N(R⁴)—W—R⁵ wherein R⁴ and R⁵ independently represent a hydrogen        atom, a C₁–C₁₈ alkyl group which may be substituted, a C₃–C₁₈        alkenyl group which may be substituted, a C₃–C₁₈ alkynyl group        which may be substituted, a C₃–C₈ cycloalkyl group which may be        substituted, or a C₆–C₁₄ aryl group which may be substituted,        and symbol “W” represents a single bond, carbonyl group,        sulfonyl group, or a nitrogen atom which may be substituted with        a C₁–C₁₈ alkyl group which may be substituted;    -   (3) compounds wherein R² is hydrogen atom, a C₁–C₈ alkyl group,        or a halogen atom;    -   (4) compounds wherein R¹ is a C₁–C₁₈ alkyl group which may be        substituted, a C₃–C₈ cycloalkyl group which may be substituted,        a C₆–C₁₄ aryl group which may be substituted, a heterocyclic        group which may be substituted by an unsubstituted alkyl group,        or a group represented by —N(R⁴)—W—R⁵ wherein R⁴ and R⁵        independently represent a hydrogen atom, a C₁–C₁₈ alkyl group        which may be substituted, or a C₆–C₁₄ aryl group which may be        substituted, and symbol “W” represents a single bond;    -   (5) compounds wherein R² is hydrogen atom;    -   (6) compounds wherein R³ represents a 3-pyridyl group which may        be substituted or a 4-pyridyl group which may be substituted;        and    -   (7) compounds wherein R³ represents a 4-pyridyl group which may        be substituted.

The pyrimidone compounds represented by the aforementioned formula (I)can be prepared, for example, according to the method explained below.

<Preparation Method 1>

(In the above scheme, R⁴ represents an alkyl group which may besubstituted and definitions of R¹–R³ are the same as those alreadydescribed.)

The 3-ketoester represented by the above formula(III) is allowed toreact with the compound represented by formula(IV) or a salt thereof toobtain the compound of the aforementioned formula(I) in the presence ofa base such as lithium tert-butoxide, sodium tert-butoxide, potassiumtert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide,lithium ethoxide, sodium ethoxide, potassium ethoxide,1,8-diazabicyclo[5,4,0]undec-7-en, triethylamine, diisopropylethylamine,dimethylbenzylamine, dimethylaniline, diethylaniline and the like.Compounds of formula(III) and formula(IV) are commercially available ormay be synthesized according to known methods of one skilled in the art.Compound of formula(I) could be derivatised into other compound offormula(I) using well known method in the art.

Examples of a solvent include, for example, alcoholic solvent such asmethanol, ethanol, 1-propanol, isopropanol, tert-butanol; ethericsolvents such as diethyl ether, tert-butyl methyl ether,tetrahydrofuran, isopropyl ether; hydrocarbonic solvents such asbenzene, toluene, xylene; halogenated solvents such as dichloromethane,chloroform, dichloroethane; aprotic polar solvents such as formamide,N,N-dimethylformamide, N,N-dimethylacetoaminde, N-methylpyrrolidone,dimethyl sulfoxide, sulfolane, hexamethylphosphoric triamide and thelike. Generally, a single solvent or a mixture of two or more solventsmay be used so as to be suitable to a base used, and the reaction may becarried out for 1 minute to 14 days at a suitable temperature rangingfrom 0° C. to 250° C. under nitrogen or argon atmosphere or in underordinary air. In the above reaction, protection or deprotection of afunctional group may sometimes be necessary. A suitable protective groupcan be chosen depending on the type of a functional group, and a methoddescribed in the literature may be applied as experimental procedures.

The compounds of the present invention have inhibitory activity againstTPK1, and they inhibit TPK1 activity in Alzheimer disease and the like,thereby suppress the neurotoxicity of Aβ and the formation of PHF andinhibit the nerve cell death. Accordingly, the compounds of the presentinvention are useful as an active ingredient of a medicament whichradically enables preventive and/or therapeutic treatment of Alzheimerdisease. In addition, the compounds of the present invention are alsouseful as an active ingredient of a medicament for preventive and/ortherapeutic treatment of ischemic cerebrovascular accidents, Downsyndrome, cerebral bleeding due to solitary cerebral amyloid angiopathy,progressive supranuclear palsy, subacute sclerosing panencephalitis,postencephalitic parkinsonism, pugilistic encephalosis, Guamparkinsonism-dementia complex, Lewy body disease, Pick's disease,corticobasal degeneration frontotemporal dementia and the like.

As the active ingredient of the medicament of the present invention, asubstance may be used which is selected from the group consisting of thecompound represented by the aforementioned formula (I) andpharmacologically acceptable salts thereof, and solvates thereof andhydrates thereof. The substance, per se, may be administered as themedicament of the present invention, however, it is desirable toadminister the medicament in a form of a pharmaceutical compositionwhich comprises the aforementioned substance as an active ingredient andone or more of pharmaceutical additives. As the active ingredient of themedicament of the present invention, two or more of the aforementionedsubstance may be used in combination. The above pharmaceuticalcomposition may be supplemented with an active ingredient of othermedicament for the treatment of Alzheimer disease and the like. A typeof the pharmaceutical composition is not particularly limited, and thecomposition may be provided as any formulation for oral or parenteraladministration. For example, the pharmaceutical composition may beformulated, for example, in the form of pharmaceutical compositions fororal administration such as granules, fine granules, powders, hardcapsules, soft capsules, syrups, emulsions, suspensions, solutions andthe like, or in the form of pharmaceutical compositions for parenteraladministrations such as injections for intravenous, intramuscular, orsubcutaneous administration, drip infusions, transdermal preparations,transmucosal preparations, nasal drops, inhalants, suppositories and thelike. Injections or drip infusions may be prepared as powderypreparations such as in the form of lyophilized preparations, and may beused by dissolving just before use in an appropriate aqueous medium suchas physiological saline. Sustained-release preparations such as thosecoated with a polymer may be directly administered intracerebrally.

Types of pharmaceutical additives used for the manufacture of thepharmaceutical composition, content rations of the pharmaceuticaladditives relative to the active ingredient, and methods for preparingthe pharmaceutical composition may be appropriately chosen by thoseskilled in the art. Inorganic or organic substances, or solid or liquidsubstances may be used as pharmaceutical additives. Generally, thepharmaceutical additives may be incorporated in a ratio ranging from 1%by weight to 90% by weight based on the weight of an active ingredient.

Examples of excipients used for the preparation of solid pharmaceuticalcompositions include, for example, lactose, sucrose, starch, talc,cellulose, dextrin, kaolin, calcium carbonate and the like. For thepreparation of liquid compositions for oral administration, aconventional inert diluent such as water or a vegetable oil may be used.The liquid composition may contain, in addition to the inert diluent,auxiliaries such as moistening agents, suspension aids, sweeteners,aromatics, colorants, and preservatives. The liquid composition may befilled in capsules made of an absorbable material such as gelatin.Examples of solvents or suspension mediums used for the preparation ofcompositions for parenteral administration, e.g. injections,suppositories, include water, propylene glycol, polyethylene glycol,benzyl alcohol, ethyl oleate, lecithin and the like. Examples of basematerials used for suppositories include, for example, cacao butter,emulsified cacao butter, lauric lipid, witepsol.

Dose and frequency of administration of the medicament of the presentinvention are not particularly limited, and they may be appropriatelychosen depending on conditions such as a purpose of preventive and/ortherapeutic treatment, a type of a disease, the body weight or age of apatient, severity of a disease and the like. Generally, a daily dose fororal administration to an adult may be 0.01 to 1,000 mg (the weight ofan active ingredient), and the dose may be administered once a day orseveral times a day as divided portions, or once in several days. Whenthe medicament is used as an injection, administrations may preferablybe performed continuously or intermittently in a daily dose of 0.001 to100 mg (the weight of an active ingredient) to an adult.

EXAMPLES

The present invention will be explained more specifically with referenceto examples. However, the scope of the present invention is not limitedto the following examples. The compound number in the examplescorresponds to that in the table above.

Example 1 Preparation of 2-(3-pyridyl)-6-(4-pyridyl)pyrimidin-4-one(Compound 125)

ethyl 3-(4-pyridyl)-3-oxopropionate (0.60 g), 3-amidinopyridinehydrochloride (0.54 g) and potassium carbonate (1.15 g) were added to 5ml of ethanol, and the mixture was heated under reflux at 75° C. for 20hours. Acetic acid was added to the reaction mixture, and the solventwas removed by distillation. The residue was added with water and thenwith acetic acid, and the resulting solid was separated by filtration,washed with water and ethyl acetate, and dried to obtain 0.39 g of thedesired compound.

Yield: 50%. Melting Point: >300° C. NMR (DMSO-d₆, δ): 7.21 (1H, s),7.59–7.63 (1H, m), 8.16 (2H, dd, J=1.5, 4.7 Hz), 8.59–8.62 (1H, m),8.74–8.79 (3H, m), 9.41 (1H, d, J=1.8 Hz).

Compounds of Example 2 to 63 were prepared in a similar manner to thatin Example 1. Physical properties of the compounds are shown below.

Example 2 Preparation of 2-methyl-6-(4-pyridyl)pyrimidin-4-one (Compound1)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 2.38 (3H, s), 6.94 (1H, s),7.98 (2H, dd, J=1.9, 4.5 Hz), 8.69 (2H, dd, J=1.9, 4.6 Hz).

Example 3 Preparation of 2-ethyl-6-(4-pyridyl)pyrimidin-4-one (Compound2)

Melting Point: 265–269° C. NMR (DMSO-d₆, δ): 1.26 (3H, t, J=7.5 Hz),2.65 (2H, t, J=7.5 Hz), 6.93 (1H, s), 7.99 (2H, dd, J=1.8, 4.6 Hz), 8.69(2H, dd, J=1.4, 4.6 Hz).

Example 4 Preparation of 2-propyl-6-(4-pyridyl)pyrimidin-4-one (Compound3)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 0.95 (3H, t, J=7.5 Hz),1.70–1.83 (2H, m), 2.61 (2H, t, J=7.8 Hz), 6.95 (1H, s), 7.99 (2H, dd,J=1.5, 4.8 Hz), 8.70 (2H, dd, J=1.8, 4.8 Hz), 12.64 (1H, bs).

Example 5 Preparation of 2-isopropyl-6-(4-pyridyl)pyrimidin-4-one(Compound 4)

Melting Point: 250–252° C. NMR (DMSO-d₆, δ): 1.27 (6H, d, J=7.2 Hz),2.86–2.95 (1H, m), 6.91 (1H, s), 8.00 (2H, dd, J=1.5, 4.2 Hz), 8.70 (2H,dd, J=1.5, 4.5 Hz).

Example 6 Preparation of 2-butyl-6-(4-pyridyl)pyrimidin-4-one (Compound5)

Melting Point: 282–285° C. NMR (DMSO-d₆, δ): 0.92 (3H, t, J=7.5 Hz),1.32–1.40 (2H, m), 1.67–1.75 (2H, m), 2.63 (2H, t, J=7.5 Hz), 6.94 (1H,s), 7.98 (2H, dd, J=1.5, 4.8 Hz), 8.70 (2H, dd, J=1.5, 4.2 Hz), 12.59(1H, bs).

Example 7 Preparation of 2-isobutyl-6-(4-pyridyl)pyrimidin-4-one(Compound 6)

Melting Point: 280–283° C. NMR (DMSO-d₆, δ): 0.95 (6H, d, J=6.6 Hz),2.16–2.25 (1H, m), 2.51 (2H, d, J=7.2 Hz), 6.93 (1H, s), 7.98 (2H, dd,J=1.8, 4.5 Hz), 8.70 (2H, dd, J=1.8, 4.5 Hz), 12.59 (1H, bs).

Example 8 Preparation of 2-pentyl-6-(4-pyridyl)pyrimidin-4-one (Compound9)

Melting Point: 238–240° C. NMR (DMSO-d₆, δ): 0.88 (3H, t, J=6.6 Hz),1.24–1.38 (4H, m), 1.78–1.90 (2H, m), 2.62 (2H, t, J=7.5 Hz), 6.93 (1H,s), 7.98 (2H, dd, J=1.5, 4.8 Hz), 8.70 (2H, dd, J=1.5, 4.5 Hz).

Example 9 Preparation of 2-hexyl-6-(4-pyridyl)pyrimidin-4-one (Compound14)

Melting Point: 226–229° C. NMR (DMSO-d₆, δ): 0.86 (3H, t, J=6.9 Hz),1.21–1.38 (6H, m), 1.68–1.78 (2H, m), 2.62 (2H, t, J=7.5 Hz), 6.93 (1H,s), 7.98 (2H, dd, J=1.8, 4.5 Hz), 8.70 (2H, dd, J=1.5, 4.5 Hz), 12.60(1H, bs).

Example 10 Preparation of 2-heptyl-6-(4-pyridyl)pyrimidin-4-one(Compound 16)

Melting Point: 219–220° C. NMR (DMSO-d₆, δ): 0.85 (3H, t, J=6.8 Hz),1.19–1.37 (8H, m), 1.69–1.78 (2H, m), 2.62 (2H, t, J=7.3 Hz), 6.92 (1H,s), 7.98 (2H, dd, J=1.4, 4.6 Hz), 8.69 (2H, dd, J=1.9, 4.6 Hz).

Example 11 Preparation of 2-octyl-6-(4-pyridyl)pyrimidin-4-one (Compound17)

Melting Point: 197–200° C. NMR (DMSO-d₆, δ): 0.84 (3H, t, J=6.9 Hz),1.10–1.37 (10H, m), 1.67–1.78 (2H, m), 2.61 (2H, t, J=7.5 Hz), 6.89 (1H,s), 7.98 (2H, dd, J=1.8, 4.5 Hz), 8.68 (2H, dd, J=1.5, 4.5 Hz).

Example 12 Preparation of 2-phenyl-6-(4-pyridyl)pyrimidin-4-one(Compound 35)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 7.14 (1H, s), 7.55–7.78 (3H,m), 8.14 (2H, dd, J=1.4, 4.6 Hz), 8.26–8.29 (2H, m), 8.75 (2H, dd,J=1.7, 4.6 Hz).

Example 13 Preparation of 2-(1-naphthyl)-6-(4-pyridyl)pyrimidin-4-one(Compound 36)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 7.20 (1H, s), 7.60–7.69 (3H,m), 7.80–7.86 (1H, m), 8.00–8.08 (3H, m), 8.10–8.18 (1H, m), 8.19–8.27(1H, m), 8.71 (H, dd, J=1.6, 4.4 Hz).

Example 14 Preparation of 6-(4-pyridyl)-2-(2-tolyl)pyrimidin-4-one(Compound 38)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 2.44 (3H, s), 7.12 (1H, s),7.29–7.38 (2H, m), 7.40–7.48 (1H, m), 7.50–7.58 (1H, m), 8.03 (2H, d,J=6.3 Hz), 8.71 (2H, d, J=6.0 Hz), 12.90 (1H, s).

Example 15 Preparation of 6-(4-pyridyl)-2-(3-tolyl)pyrimidin-4-one(Compound 39)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 2.42 (3H, s), 7.11 (1H, s),7.44–7.49 (2H, m), 8.01–8.09 (2H, m), 8.12 (2H, dd, J=1.5, 4.5 Hz), 8.75(2H, dd, J=1.5, 4.5 Hz).

Example 16 Preparation of 6-(4-pyridyl)-2-(4-tolyl)pyrimidin-4-one(Compound 40)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 2.41 (3H, s), 7.08 (1H, s),7.38 (2H, d, J=8.1 Hz), 8.12 (2H, dd, J=1.5, 4.5 Hz), 8.18 (2H, d, J=8.1Hz), 8.74 (2H, d, J=1.5, 4.8 Hz).

Example 17 Preparation of2-(4-fluorophenyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 46)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 7.06 (1H, s), 7.35–7.41 (2H,m), 8.11 (2H, dd, J=1.7, 4.5 Hz), 8.36–8.39 (2H, m), 8.73 (2H, dd,J=1.6, 4.6 Hz).

Example 18 Preparation of2-(4-chlorophenyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 49)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 7.15 (1H, s), 7.63 (2H, d,J=8.7 Hz), 8.13 (2H, dd, J=1.5, 4.5 Hz), 8.31 (2H, d, J=8.7 Hz), 8.75(2H, d, J=6.0 Hz).

Example 19 Preparation of 2-(3-bromophenyl)-6-(4-pyridyl)pyrimidin-4-one(Compound 51)

Melting Point: 285–287° C. NMR (DMSO-d₆, δ): 7.19 (1H, s), 7.52–7.57(1H, m), 7.81–7.84 (1H, m), 8.14 (2H, dd, J=1.5, 4.5 Hz), 8.28–8.32 (1H,m), 8.42–8.48 (1H, m), 8.75 (2H, dd, J=1.5, 4.8 Hz).

Example 20 Preparation of2-(3-methoxyphenyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 54)

Melting Point: 262–264° C. NMR (DMSO-d₆, δ): 3.87 (3H, s), 7.11 (1H, s),7.16–7.20 (1H, m), 7.45–7.51 (1H, m), 7.82 (1H, s), 7.87–7.90 (1H, m),8.12 (2H, dd, J=1.5, 4.5 Hz), 8.74 (2H, dd, J=1.5, 4.5 Hz).

Example 21 Preparation of2-(3-ethoxyphenyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 57)

Melting Point: 250–253° C. NMR (DMSO-d₆, δ): 1.38 (3H, t, J=6.9 Hz),4.15 (2H, q, J=6.9 Hz), 7.13 (1H, s), 7.15–7.19 (1H, m), 7.44–7.50 (1H,m), 7.80 (1H, s), 7.84–7.88 (1H, m), 8.13 (2H, dd, J=1.5, 4.8 Hz), 8.75(2H, dd, J=1.5, 4.8 Hz), 12.92 (1H, bs).

Example 22 Preparation of 2-(3-cyanophenyl)-6-(4-pyridyl)pyrimidin-4-one(Compound 60)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 7.22 (1H, s), 7.76–7.81 (1H,m), 8.07–8.10 (1H, m), 8.18 (2H, dd, J=1.2, 4.5 Hz), 8.57–8.62 (1H, m),8.71–8.77 (3H, m).

Example 23 Preparation of 2-(4-cyanophenyl)-6-(4-pyridyl)pyrimidin-4-one(Compound 61)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 7.25 (1H, s), 8.06 (2H, d,J=8.4 Hz), 8.16 (2H, dd, J=1.5, 4.5 Hz), 8.47 (2H, d, J=8.4 Hz), 8.76(2H, d, J=1.5, 4.8 Hz).

Example 24 Preparation of 2-(4-nitrophenyl)-6-(4-pyridyl)pyrimidin-4-one(Compound 64)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 7.30 (1H, s), 8.17 (2H, dd,J=1.1, 4.7 Hz), 8.40 (2H, d, J=8.8 Hz), 8.56 (2H, d, J=8.8 Hz), 8.76(2H, d, J=5.9 Hz).

Example 25 Preparation of6-(4-pyridyl)-2-(3-trifluorophenyl)-pyrimidin-4-one (Compound 66)

NMR (DMSO-d₆, δ): 7.18 (1H, s), 7.78–7.84 (1H, m), 7.95–8.00 (1H, m),8.13 (2H, dd, J=1.6, 4.5 Hz), 8.60–8.63 (2H, m), 8.76 (2H, dd, J=1.6,4.5 Hz).

Example 26 Preparation of6-(4-pyridyl)-2-(4-trifluorophenyl)-pyrimidin-4-one (Compound 67)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 7.26 (1H, s), 7.95 (2H, d,J=8.4 Hz), 8.15 (2H, dd, J=1.2, 4.8 Hz), 8.50 (2H, d, J=8.1 Hz), 8.77(2H, dd, J=0.9, 4.8 Hz), 13.09 (1H, bs).

Example 27 Preparation of2-(3-(dimethylaminomethyl)phenyl)-6-(4-pyridyl)pyrimidin-4-onedihydrochloride (Compound 75)

Melting Point: 185–190° C. NMR (DMSO-d₆, δ): 2.75 (6H, d, J=4.8 Hz),4.40 (2H, d, J=5.1 Hz), 7.36 (1H, s), 7.68 (1H, t, J=7.8 Hz), 7.85 (1H,d, J=7.8 Hz), 8.33 (1H, d, J=7.8 Hz), 8.51 (1H, s), 8.59 (2H, d, J=6.6Hz), 8.94 (2H, d, J=6.3 Hz), 10.98 (1H, bs).

Example 28 Preparation of 2-benzyl-6-(4-pyridyl)pyrimidin-4-one(Compound 77)

Melting Point: 290–294° C. NMR (DMSO-d₆, δ): 3.96 (2H, s), 6.97 (1H, s),7.26–7.42 (5H, m), 7.96 (2H, dd, J=1.5, 4.8 Hz), 8.69 (2H, dd, J=1.5,4.5 Hz), 12.87 (1H, bs).

Example 29 Preparation of2-(2-methylbenzyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 78)

Melting Point: 260–263° C. NMR (DMSO-d₆, δ): 2.39 (3H, s), 3.99 (2H, s),6.98 (1H, s), 7.10–7.20 (3H, m), 7.21–7.29 (1H, m), 7.89 (2H, dd, J=1.5,4.5 Hz), 8.67 (2H, dd, J=1.5, 4.5 Hz), 12.83 (1H, bs).

Example 30 Preparation of2-(3-methylbenzyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 79)

Melting Point: 245–247° C. NMR (DMSO-d₆, δ): 2.29 (3H, s), 3.92 (2H, s),6.97 (1H, s), 7.05–7.09 (1H, m), 7.17–7.26 (3H, m), 7.96 (2H, dd, J=1.8,4.5 Hz), 8.69 (2H, dd, J=1.5, 4.5 Hz), 12.85 (1H, bs).

Example 31 Preparation of2-(4-methylbenzyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 80)

Melting Point: 267–270° C. NMR (DMSO-d₆, δ): 2.26 (3H, s), 3.91 (2H, s),6.96 (1H, s), 7.14 (2H, d, J=7.9 Hz), 7.29 (2H, d, J=8.1 Hz), 7.96 (2H,dd, J=1.5, 4.6 Hz), 8.69 (2H, dd, J=1.8, 4.6 Hz).

Example 32 Preparation of2-(4-methoxybenzyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 83)

Melting Point: 255–257° C. NMR (DMSO-d₆, δ): 3.72 (3H, s), 3.88 (2H, s),6.90 (2H, d, J=11.7 Hz), 6.95 (1H, s), 7.32 (2H, d, J=11.7 Hz), 7.96(2H, dd, J=1.5, 4.5 Hz), 8.69 (2H, dd, J=1.5, 4.8 Hz), 12.83 (1H, bs).

Example 33 Preparation of2-(4-chlorobenzyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 86)

Melting Point: 277–280° C. NMR (DMSO-d₆, δ): 3.97 (2H, s), 6.96 (1H, s),7.37–7.41 (1H, m), 7.94 (2H, dd, J=1.6, 4.4 Hz), 8.68 (2H, dd, J=1.6,4.5 Hz).

Example 34 Preparation of2-(2,4-dichlorobenzyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 88)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 4.14 (2H, s), 7.00 (1H, s),7.44–7.52 (2H, m), 7.66 (1H, d, J=2.1 Hz), 7.80 (2H, dd, J=1.5, 4.5 Hz),8.65 (2H, dd, J=1.5, 4.5 Hz), 12.91 (1H, bs).

Example 35 Preparation of 2-(2-phenylethyl)-6-(4-pyridyl)pyrimidin-4-one(Compound 93)

Melting Point: 264–266° C. NMR (DMSO-d₆, δ): 2.91–2.97 (2H, m),3.06–3.11 (2H, m), 6.95 (1H, s), 7.17–7.22 (1H, m), 7.25–7.33 (4H, m),8.00 (2H, dd, J=1.5, 4.5 Hz), 8.70 (2H, dd, J=1.5, 4.8 Hz).

Example 36 Preparation of2-(3-phenylpropyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 94)

Melting Point: 238–248° C. NMR (DMSO-d₆, δ): 2.01–2.11 (2H, m),2.63–2.70 (4H, m), 6.94 (1H, s), 7.16–7.32 (4H, m), 7.99 (2H, dd, J=1.5,4.8 Hz), 8.70 (2H, dd, J=1.5, 4.8 Hz), 12.60 (1H, bs).

Example 37 Preparation of 2-(2-pyridyl)-6-(4-pyridyl)pyrimidin-4-one(Compound 124)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 7.22 (1H, s), 7.66–7.71 (1H,m), 8.08–8.18 (3H, m), 8.54–8.59 (1H, m), 8.75–8.80 (3H, m).

Example 38 Preparation of 2,6-di(4-pyridyl)pyrimidin-4-one (Compound126)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 7.29 (1H, s), 8.17 (2H, dd,J=1.4, 4.6 Hz), 8.22 (2H, d, J=6.2 Hz), 8.76 (2H, d, J=6.2 Hz), 8.82(2H, dd, J=1.6, 4.6 Hz).

Example 39 Preparation of 2-(2-pyrazinyl)-6-(4-pyridyl)pyrimidin-4-one(Compound 128)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 6.73 (1H, s), 8.05 (2H, dd,J=1.4, 4.7 Hz), 8.65–8.74 (4H, m), 9.52 (1H, s).

Example 40 Preparation of6-(4-pyridyl)-2-(2-pyridylmethyl)pyrimidin-4-one (Compound 45)

Melting Point: 249–252° C. NMR (DMSO-d₆, δ): 4.19 (2H, s), 7.00 (1H, s),7.25–7.33 (1H, m), 7.41–7.49 (1H, m), 7.77–7.82 (1H, m), 7.90 (2H, dd,J=1.5, 4.5 Hz), 8.48–8.51 (1H, m), 8.67 (2H, dd, J=1.5, 4.8 Hz), 12.84(1H, bs).

Example 41 Preparation of6-(4-pyridyl)-2-(3-pyridylmethyl)pyrimidin-4-one (Compound 146)

Melting Point: 267–269° C. NMR (DMSO-d₆, δ): 4.01 (2H, s), 6.94 (1H, s),7.36–7.42 (1H, m), 7.80–7.85 (1H, m), 7.91 (2H, dd, J=1.7, 4.6 Hz),8.46–8.50 (1H, m), 8.59–8.62 (1H, m), 8.67 (2H, dd, J=1.4, 4.6 Hz).

Example 42 Preparation of6-(4-pyridyl)-2-(2-thienylmethyl)pyrimidin-4-one (Compound 150)

Melting Point: 268–270° C. NMR (DMSO-d₆, δ): 4.19 (2H, s), 6.98–7.01(2H, m), 6.99 (1H, s), 7.06–7.07 (1H, m), 7.44 (1H, dd, J=1.2, 5.2 Hz),7.99 (2H, dd, J=1.5, 4.6 Hz), 8.71 (2H, dd, J=1.7, 4.6 Hz).

Example 43 Preparation of 2-amino-6-(4-pyridyl)pyrimidin-4-one (Compound157)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 6.28 (1H, s), 6.73 (2H, bs),7.87 (2H, dd, J=1.5, 4.8 Hz), 8.64 (2H, dd, J=1.5, 4.8 Hz), 10.99 (1H,bs).

Example 44 Preparation of 2-dimethylamino-6-(4-pyridyl)pyrimidin-4-one(Compound 169)

Melting Point: >240° C. NMR (DMSO-d₆, δ): 3.14 (6H, s), 6.31 (1H, s),7.94 (2H, dd, J=1.5, 4.8 Hz), 8.67 (2H, dd, J=1.5, 4.8 Hz).

Example 45 Preparation of 5-methyl-2-phenyl-6-(4-pyridyl)pyrimidin-4-one(Compound 183)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 2.06 (3H, s), 7.49–7.59 (3H,m), 7.64 (2H, dd, J=1.5, 4.5 Hz), 8.12–8.15 (2H, m), 8.72 (2H, dd,J=1.5, 4.5 Hz), 12.93 (1H, bs).

Example 46 Preparation of5-methyl-2-(3-phenylpropyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 184)

Melting Point: 141–143° C. NMR (DMSO-d₆, δ): 1.93–2.03 (2H, m), 1.95(3H, s), 2.55–2.66 (4H, m), 7.14–7.30 (5H, m), 7.51 (2H, dd, J=1.5, 4.5Hz), 8.68 (2H, dd, J=1.5, 4.2 Hz), 12.50 (1H, bs).

Example 47 Preparation of 5-ethyl-2-phenyl-6-(4-pyridyl)pyrimidin-4-one(Compound 185)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 1.09 (3H, t, J=7.5 Hz), 2.42(2H, q, J=7.5 Hz), 7.48–7.59 (5H, m), 8.09–8.12 (2H, m), 8.72 (2H, dd,J=1.5, 4.2 Hz), 12.87 (1H, bs).

Example 48 Preparation of5-ethyl-2-(3-phenylpropyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 186)

Melting Point: 161–163° C. NMR (DMSO-d₆, δ): 1.02 (3H, t, J=7.5 Hz),1.89–2.01 (2H, m), 2.31 (2H, q, J=7.5 Hz), 2.54–2.66 (4H, m), 7.14–7.29(5H, m), 7.43 (2H, dd, J=1.2, 4.5 Hz), 8.67 (2H, d, J=1.5, 4.8 Hz),12.50 (1H, bs).

Example 49 Preparation of 2-phenyl-5-propyl-6-(4-pyridyl)pyrimidin-4-one(Compound 187)

Melting Point: 274–275° C. NMR (DMSO-d₆, δ): 0.81 (3H, t, J=7.5 Hz),1.49 (2H, m), 2.39 (2H, t, J=7.5 Hz), 7.48–7.60 (5H, m), 8.10 (2H, d,J=7.2 Hz), 8.72 (2H, dd, J=1.5, 4.5 Hz), 12.91 (1H, bs).

Example 50 Preparation of2-(3-phenylpropyl)-5-propyl-6-(4-pyridyl)pyrimidin-4-one (Compound 188)

Melting Point: 148–149° C. NMR (DMSO-d₆, δ): 0.76 (3H, t, J=7.5 Hz),1.14 (2H, m), 1.96 (2H, m), 2.27 (2H, t, J=7.8 Hz), 2.51–2.65 (4H, m),7.13–7.20 (3H, m), 7.24–7.29 (2H, m), 7.41 (2H, dd, J=1.5, 4.5 Hz), 8.67(2H, dd, J=1.5, 4.5 Hz), 12.51 (1H, bs).

Example 51 Preparation of 5-butyl-2-phenyl-6-(4-pyridyl)pyrimidin-4-one(Compound 191)

Melting Point: 269–270° C. NMR (DMSO-d₆, δ): 0.78 (3H, t, J=7.5 Hz),1.21 (2H, m), 1.46 (2H, m), 2.42 (2H, t, J=8.7 Hz), 7.48–7.60 (5H, m),8.11 (2H, d, J=7.2 Hz), 8.71 (2H, dd, J=1.5, 4.5 Hz).

Example 52 Preparation of5-butyl-2-(3-phenylpropyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 192)

Melting Point: 146–147° C. NMR (DMSO-d₆, δ): 0.75 (3H, t, J=7.2 Hz),1.17 (2H, m), 1.40 (2H, m), 1.96 (2H, m), 2.49 (2H, t, J=7.2 Hz),2.50–2.65 (4H, m), 7.13–7.20 (3H, m), 7.24–7.29 (2H, m), 7.42 (2H, dd,J=1.5, 4.5 Hz), 8.67 (2H, dd, J=1.5, 4.5 Hz), 12.51 (1H, bs).

Example 53 Preparation of 5-benzyl-2-methyl-6-(4-pyridyl)pyrimidin-4-one(Compound 211)

NMR (DMSO-d₆, δ): 2.33 (3H, s), 3.73 (2H, s), 6.91–6.99 (2H, m),7.11–7.29 (3H, m), 7.35 (2H, d, J=4.5 Hz), 7.62 (2H, d, J=5.7 Hz), 12.68(1H, bs).

Example 54 Preparation of 5-benzyl-2-phenyl-6-(4-pyridyl)pyrimidin-4-one(Compound 212)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 7.04–7.07 (2H, m), 7.15–7.26(3H, m), 7.48–7.59 (5H, m), 8.13–8.16 (2H, m), 8.67 (2H, d, J=4.8 Hz),13.02 (1H, bs).

Example 55 Preparation of6-(2-ethylpyridin-4-yl)-2-(3-phenylpropyl)pyrimidin-4-one (Compound 256)

Melting Point: 139–141° C. NMR (DMSO-d₆, δ): 1.26 (3H, t, J=7.5 Hz),2.06 (2H, m), 2.63–2.70 (4H, m), 2.82 (2H, q, J=7.5 Hz), 6.90 (1H, s),7.18–7.30 (5H, m), 7.78 (1H, d, J=6.9 Hz), 7.84 (1H, s), 8.58 (1H, d,J=5.1 Hz).

Example 56 Preparation of6-(2-methoxypyridin-4-yl)-2-(3-phenylpropyl)pyrimidin-4-one (Compound268)

Melting Point: 179–181° C. NMR (DMSO-d₆, δ): 2.09 (2H, m), 2.62–2.67(4H, m), 3.89 (3H, s), 6.89 (1H, s), 7.12–7.38 (5H, m), 7.41 (1H, s),8.27 (1H, d, J=5.4 Hz), 12.55 (1H, bs).

Example 57 Preparation of6-(2-methoxypyridin-4-yl)-2-(4-pyridyl)pyrimidin-4-one (Compound 269)

Melting Point: 273–274° C. NMR (DMSO-d₆, δ): 3.93 (3H, s), 7.24 (1H,bs), 7.58 (1H, s), 7.74 (1H, d, J=5.4 Hz), 8.20 (2H, d, J=6.0 Hz), 8.33(2H, d, J=5.4 Hz), 8.80 (2H, dd, J=1.5, 4.5 Hz).

Example 58 Preparation of6-(2-chloropyridin-4-yl)-2-(3-phenylpropyl)pyrimidin-4-one (Compound283)

Melting Point: 177–179° C. NMR (DMSO-d₆, δ): 2.06 (2H, m), 2.63–2.70(4H, m), 7.02 (1H, s), 7.18–7.31 (5H, m), 8.02 (1H, dd, J=1.5, 5.1 Hz),8.08 (1H, d, J=1.5 Hz), 8.53 (1H, d, J=5.1 Hz), 12.63 (1H, bs).

Example 59 Preparation of6-(2-chloropyridin-4-yl)-2-(4-pyridyl)pyrimidin-4-one (Compound 284)

Melting Point: 179–181° C. NMR (DMSO-d₆, δ): 7.35 (1H, bs), 8.19–8.23(3H, m), 8.27 (1H, s), 8.59 (1H, d, J=4.8 Hz), 8.81 (2H, dd, J=1.5, 4.5Hz).

Example 60 Preparation of 2-methyl-6-(3-pyridyl)pyrimidin-4-one(Compound 297)

Melting Point: 261–263° C. NMR (DMSO-d₆, δ): 2.38 (3H, s), 6.87 (1H, s),7.43–7.53 (1H, m), 8.36–8.40 (1H, m), 8.65–8.67 (1H, m), 9.20 (1H, d,J=2.1 Hz), 12.57 (1H, bs).

Example 61 Preparation of 2-phenyl-6-(3-pyridyl)pyrimidin-4-one(Compound 298)

Melting Point: 233–236° C. NMR (DMSO-d₆, δ): 7.05 (1H, s), 7.54–7.60(4H, m), 8.26–8.30 (2H, m), 8.52–8.55 (1H, m), 8.69–8.72 (1H, m), 9.36(1H, d, J=2.1 Hz).

Example 62 Preparation of 6-(3-pyridyl)-2-(4-pyridyl)pyrimidin-4-one(Compound 300)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 7.23 (1H, s), 7.55–7.59 (1H,m), 8.23 (2H, dd, J=1.2, 4.5 Hz), 8.56–8.60 (1H, m), 8.71–8.74 (1H, m),8.81 (2H, d, J=1.5, 4.8 Hz), 9.39 (1H, d, J=2.1 Hz), 13.03 (1H, bs).

Example 63 Preparation of 2-dimethylamino-6-(3-pyridyl)pyrimidin-4-one(Compound 301)

Melting Point: 263–266° C. NMR (DMSO-d₆, δ): 3.14 (6H, s), 6.25 (1H,bs), 7.45–7.50 (1H, m), 8.34–8.37 (1H, m), 8.62–8.65 (1H, m), 9.19 (1H,d, J=1.8 Hz).

Example 64 Preparation of 5-bromo-2-phenyl6-(4-pyridyl)pyrimidin-4-one(Compound 233)

2-Phenyl-6-(4-pyridyl)pyrimidin-4-one (0.61 g) obtained in Example 12was dissolved in 3 ml of acetic acid, and then the mixture was addedwith 0.48 g of N-bromosuccinimide and heated at 90° C. for 1 hour. Waterwas added to the reaction mixture, and solid mass was separated byfiltration. The solid was washed with water, acetone, and ethyl acetate,and dried to obtain 0.74 g of the desired compound.

Yield: 93%. Melting Point: >300° C. NMR (DMSO-d₆, δ): 7.51–7.65 (3H, m),7.73 (2H, dd, J=1.5, 4.5 Hz), 8.13 (2H, d, J=7.2 Hz), 8.75 (2H, dd,J=1.5, 4.5 Hz), 13.45 (1H, bs).

Compounds of Example 65 to 98 were prepared in a similar manner to thatin Example 1. Physical properties of the compounds are shown below.

Example 65 Preparation of 5-chloro-2-phenyl-6-(4-pyridyl)pyrimidin-4-one(Compound 230)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 7.52–7.62 (3H, m), 7.79 (2H,dd, J=1.5, 4.5 Hz), 8.12–8.16 (2H, m), 8.77 (2H, dd, J=1.5, 4.5 Hz),13.51 (1H, bs).

Example 66 Preparation of 2-amino-5-chloro-6-(4-pyridyl)pyrimidin-4-one(Compound 232)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 6.86 (2H, bs), 7.56 (2H, dd,J=1.5, 4.5 Hz), 8.67 (2H, dd, J=1.5, 4.5 Hz), 11.59 (1H, bs).

Example 67 Preparation of 2-benzoylamino-6-(4-pyridyl)pyrimidin-4-one(Compound 179)

Melting Point: 257–259° C. NMR (DMSO-d₆, δ): 7.25 (1H, bs), 7.29 (1H,s), 7.62–7.67 (2H, m), 7.80 (1H, t, J=7.5 Hz), 8.02 (2H, dd, J=1.8, 4.5Hz), 8.12–8.15 (2H, m), 8.75 (2H, dd, J=1.8, 4.5 Hz).

Example 68 Preparation of2-(2-chlorobenzyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 84)

Melting Point: 264–266° C. NMR (DMSO-d₆, δ): 4.14 (2H, s), 7.00 (1H, s),7.31–7.50 (4H, m), 7.81 (2H, d, J=6.0 Hz), 8.64 (2H, d, J=5.7 Hz), 12.91(1H, bs).

Example 69 Preparation of 2-(1-piperidino)-6-(4-pyridyl)pyrimidin-4-one(Compound 141)

Melting Point: 267–268° C. NMR (DMSO-d₆, δ): 1.50–1.59 (6H, m), 3.67(4H, m), 6.29 (1H, s), 7.89 (2H, d, J=5.7 Hz), 8.62 (2H, d, J=5.7 Hz).

Example 70 Preparation of2-(4-methyl-1-piperazino)-6-(4-pyridyl)pyrimidin-4-one (Compound 144)

Melting Point: 275° C. decomposition. NMR (DMSO-d₆, δ): 2.77, 2.79 (3H,s), 3.00–3.20 (2H, m), 3.40–3.58 (4H, m), 4.62–4.78 (2H, m), 6.80 (1H,br), 8.45 (2H, d, J=6.6 Hz), 8.92 (2H, d, J=6.6 Hz), 11.28 (1H, br).

Example 71 Preparation of 2-(diethylamino)-6-(4-pyridyl)pyrimidin-4-one(Compound 170)

Melting Point: 199–200° C. NMR (DMSO-d₆, δ): 1.15 (6H, t, J=7.0 Hz),3.60 (4H, q, J=7.0 Hz), 6.32 (1H, s), 7.93 (2H, d, J=5.8 Hz), 8.67 (2H,d, J=5.7 Hz).

Example 72 Preparation of 6-(4-chloro-3-pyridyl)-2-phenylpyrimidin-4-one(Compound 320)

Melting Point: 286–288° C. NMR (DMSO-d₆, δ): 7.09 (1H, s), 7.54–7.69(4H, m), 8.25–8.28 (2H, m), 8.60 (1H, dd, J=2.5, 8.4 Hz), 9.19 (1H, d,J=2.3 Hz).

Example 73 Preparation of6-(4-chloro-3-pyridyl)-2-(3-phenylpropyl)pyrimidin-4-one (Compound 321)

Melting Point: 194–196° C. NMR (DMSO-d₆, δ): 2.01–2.11 (2H, m),2.62–2.69 (4H, m), 6.89 (1H, s), 7.15–7.31 (5H, m), 7.63 (1H, d, J=8.3Hz), 8.44 (1H, dd, J=2.5, 8.4 Hz), 9.05 (1H, d, J=2.3 Hz).

Example 74 Preparation of 2-phenyl-6-(2-pyridyl)pyrimidin-4-one(Compound 326)

Melting Point: 268–271° C. NMR (DMSO-d₆, δ): 7.22 (1H, s), 7.51–7.61(4H, m), 7.97–8.03 (1H, m), 8.28–8.36 (2H, m), 8.49 (1H, d, J=7.5 Hz),8.73 (1H, d, J=4.2 Hz).

Example 75 Preparation of2-(3-phenylpropyl)-6-(2-pyridyl)pyrimidin-4-one (Compound 327)

Melting Point: 168–170° C. NMR (DMSO-d₆, δ): 2.03–2.13 (2H, m),2.64–2.71 (4H, m), 7.06 (1H, s), 7.17–7.33 (5H, m), 7.49–7.53 (1H, m),7.94–8.00 (1H, m), 8.29 (1H, d, J=8.1 Hz), 8.69 (1H, d, J=3.9 Hz), 12.55(1H, bs).

Example 76 Preparation of 2-(3-biphenyl)-6-(4-pyridyl)pyrimidin-4-one(Compound 369)

Melting Point: 296–298° C. NMR (DMSO-d₆, δ): 7.10 (1H, s), 7.40–7.47(1H, m), 7.51–7.56 (2H, m), 7.62–7.70 (1H, m), 7.82–7.85 (2H, m),7.90–7.93 (1H, m), 8.14 (2H, d, J=5.8 Hz), 8.29–8.34 (1H, m), 8.53 (1H,s), 8.74 (2H, d, J=5.8 Hz).

Example 77 Preparation of2-(4-propylbenzyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 381)

Melting Point: 249–252° C. NMR (DMSO-d₆, δ): 0.87 (3H, t, J=6.9 Hz),1.52–1.59 (2H, m), 2.52 (2H, t, J=7.2 Hz), 3.91 (2H, s), 6.97 (1H, s),7.15 (2H, d, J=8.1 Hz), 7.30 (2H, d, J=8.1 Hz), 7.97 (2H, d, J=6.3 Hz),8.69 (2H, d, J=6.0 Hz), 12.86 (1H, bs).

Example 78 Preparation of 2-(4-butylbenzyl)-6-(4-pyridyl)pyrimidin-4-one(Compound 383)

Melting Point: 241–243° C. NMR (DMSO-d₆, δ): 0.87 (3H, t, J=7.2 Hz),1.24–1.31 (2H, m), 1.47–1.57 (2H, m), 2.53 (2H, t, J=7.5 Hz), 3.91 (2H,s), 6.96 (1H, s), 7.15 (2H, d, J=8.1 Hz), 7.30 (2H, d, J=7.8 Hz), 7.96(2H, d, J=5.7 Hz), 8.69 (2H, d, J=5.7 Hz), 12.85 (1H, bs).

Example 79 Preparation of2-(N-benzyl-N-methylamino)-6-(4-pyridyl)pyrimidin-4-one (Compound 404)

Melting Point: 223–224° C. NMR (DMSO-d₆, δ): 3.11 (3H, s), 4.92 (2H, s),6.40 (1H, s), 7.24–7.38 (5H, m), 7.95 (2H, d, J=5.7 Hz), 8.66 (2H, d,J=5.7 Hz), 11.36 (1H, bs).

Example 80 Preparation of 2-benzylamino-6-(4-pyridyl)pyrimidin-4-one(Compound 397)

Melting Point: 230–232° C. NMR (DMSO-d₆, δ): 4.61 (d, J=5.7 Hz, 2H),6.34 (s, 1H), 7.12 (br, 1H), 7.23–7.41 (m, 5H), 7.90 (dd, J=1.5 Hz, 4.5Hz, 2H), 8.65 (dd, J=1.5 Hz, 4.5 Hz, 2H), 11.02 (br, 1H).

Example 81 Preparation of2-(3,3-diphenylpropylamino)-6-(4-pyridyl)pyrimidin-4-one (Compound 438)

Melting Point: 227–228° C. NMR (DMSO-d₆, δ): 2.33 (m, 2H), 4.04 (t,J=7.5 Hz, 2H), 6.28 (s, 1H), 6.70 (br, 1H), 7.16–7.36 (m, 10H), 7.77 (d,J=6.0 Hz, 2H), 8.64 (dd, J=1.2 Hz, 6.0 Hz, 2H), 10.93 (br, 1H).

Example 82 Preparation of 2-(4-morpholinyl)-6-(4-pyridyl)pyrimidin-4-one(Compound 142)

Melting Point: 285–288° C. NMR (DMSO-d₆, δ): 3.70 (m, 8H), 6.44 (br,1H), 7.95 (d, J=6.0 Hz, 2H), 8.66 (dd, J=1.5 Hz, 6.0 Hz, 2H), 11.44 (br,1H).

Example 83 Preparation of 2-cyclohexyl-6-(4-pyridyl)pyrimidin-4-one(Compound 33)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 1.20–1.40 (m, 3H), 1.55–1.75(m, 3H), 1.78–1.93 (m, 4H), 2.63 (m, 1H), 2.92 (s, 1H), 7.99 (dd, J=1.5Hz, 4.8 Hz, 2H), 8.70 (dd, J=1. Hz, 4.8 Hz, 2H), 12.49 (br, 1H).

Example 84 Preparation of2-(N-isobutyl-N-methylamino)-6-(4-pyridyl)pyrimidin-4-one (Compound 440)

Melting Point: 212–213° C. NMR (DMSO-d₆, δ): 0.89 (d, J=6.6 Hz, 6H),2.06 (m, 1H), 3.12 (s, 3H), 3.46 (d, J=7.2 Hz, 2H), 6.29 (br, 1H), 7.93(d, J=6.0 Hz, 2H), 8.67 (dd, J=1.5 Hz, 6.0 Hz, 2H), 11.10 (br, 1H).

Example 85 Preparation of 2-dipropylamino-6-(4-pyridyl)pyrimidin-4-one(Compound 171)

Melting Point: 208–209° C. NMR (DMSO-d₆, δ): 0.90 (t, J=7.5 Hz, 6H),1.60 (m, 4H), 3.50 (t, J=7.5 Hz, 4H), 6.30 (br, 1H), 7.92 (d, J=6.0 Hz,2H), 8.67 (d, J=6.0 Hz, 2H), 11.20 (br, 1H).

Example 86 Preparation of2-(3-hydroxypropylamino)-6-(4-pyridyl)pyrimidin-4-one (Compound 401)

Melting Point: 217–219° C. NMR (DMSO-d₆, δ): 1.73 (m, 2H), 3.44–3.53 (m,4H), 4.59 (t, J=5.1 Hz, 1H), 6.31 (s, 1H), 6.64 (br, 1H), 7.93 (dd,J=1.5 Hz, 6.0 Hz, 2H), 8.66 (dd, J=1.5 Hz, 6.0 Hz, 2H), 10.94 (br, 1H).

Example 87 Preparation of2-(1-pyrrolidinyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 140)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 1.92 (m, 4H), 3.53 (m, 4H),6.28 (brs, 1H), 7.94 (dd, J=1.5 Hz, 6.0 Hz, 2H), 8.66 (dd, J=1.5 Hz, 6.0Hz, 2H), 11.14 (br, 1H).

Example 88 Preparation of2-cyclohexylmethylamino-6-(4-pyridyl)pyrimidin-4-one (Compound 436)

Melting Point: 203–205° C. NMR (DMSO-d₆, δ): 0.80–1.05 (m, 2H),1.05–1.35 (m, 3H), 1.55–1.80 (m, 6H), 3.25 (m, 2H), 6.30 (s, 1H), 6.65(br, 1H), 7.91 (dd, J=1.5 Hz, 4.5 Hz, 2H), 8.66 (dd, J=1.5 Hz, 4.5 Hz,2H), 10.78 (br, 1H).

Example 89 Preparation of2-(ethylphenylamino)-6-(4-pyridyl)pyrimidin-4-one (Compound 428)

Melting Point: 232–235° C. NMR (DMSO-d₆, δ): 1.19 (t, J=7.5 Hz, 3H),2.59 (q, J=7.5 Hz, 2H), 6.58 (s, 1H), 7.23 (d, J=8.4 Hz, 2H), 7.60 (d,J=8.4 Hz, 2H), 7.95 (d, J=6.0 Hz, 2H), 8.71 (dd, J=1.2 Hz, 6.0 Hz, 2H),8.89 (br, 1H), 10.91 (br, 1H).

Example 90 Preparation of2-(butoxyphenylamino)-6-(4-pyridyl)pyrimidin-4-one (Compound 434)

Melting Point: 207–209° C. NMR (DMSO-d₆, δ): 0.94 (t, J=7.5 Hz, 3H),1.42 (m, 2H), 1.70 (m, 2H), 3.96 (t, J=6.6 Hz, 2H), 6.54 (s, 1H), 6.95(d, J=9.0 Hz, 2H), 7.56 (d, J=9.0 Hz, 2H), 7.92 (d, J=6.0 Hz, 2H), 8.69(d, J=6.0 Hz, 2H), 8.85 (br, 1H), 10.93 (br, 1H).

Example 91 Preparation of2-(bromophenylamino)-6-(4-pyridyl)pyrimidin-4-one (Compound 421)

Melting Point: 289–291° C. NMR (DMSO-d₆, δ): 6.69 (br, 1H), 7.23 (m,1H), 7.33 (t, J=8.1 Hz, 1H), 7.65 (m, 1H), 7.96 (d, J=5.7 Hz, 2H), 8.15(s, 1H), 8.72 (d, J=5.7 Hz, 2H). m.p.: 289–291° C.

Example 92 Preparation of 2-phenylamino-6-(4-pyridyl)pyrimidin-4-one(Compound 168)

Melting Point: 252–253° C. NMR (DMSO-d₆, δ): 6.62 (s, 1H), 7.08 (t,J=7.8 Hz, 1H), 7.39 (d, J=7.8 Hz, 2H), 7.71 (d, J=7.8 Hz, 2H), 7.95 (d,J=6.0 Hz, 2H), 8.71 (d, J=6.0 Hz, 2H), 9.00 (br, 1H), 10.95 (br, 1H).

Example 93 Preparation of2-(3-methoxyphenylamino)-6-(4-pyridyl)pyrimidin-4-one (Compound 430)

Melting Point: 155° C. NMR (DMSO-d₆, δ): 3.79 (s, 3H), 6.59–6.65 (m,2H), 7.05–7.30 (m, 3H), 7.54 (s, 1H), 7.96 (d, J=5.7 Hz, 2H), 8.71 (d,J=5.7 Hz, 2H).

Example 94 Preparation of2-(3,3-diphenylpropyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 396)

Melting Point: 297–299° C. NMR (DMSO-d₆, δ): 2.49–2.55 (m, 4H), 4.05 (m,1H), 6.86 (s, 1H), 7.10–7.20 (m, 2H), 7.26–7.37 (m, 8H), 7.97 (dd, J=1.5Hz, 4.5 Hz, 2H), 8.69 (dd, J=1.5 Hz, 4.5 Hz, 2H).

Example 95 Preparation of2-(2-naphthylmethyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 97)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 4.15 (s, 2H), 6.99 (s, 1H),7.48–7.52 (m, 2H), 7.58 (d, J=10.2 Hz, 1H), 7.87–7.92 (m, 4H), 7.96 (dd,J=1.5 Hz, 4.5 Hz, 2H), 8.68 (dd, J=1.5 Hz, 4.5 Hz, 2H), 12.96 (br, 1H).

Example 96 Preparation of2-(3-phenylbenzyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 379)

Melting Point: 234–237° C. NMR (DMSO-d₆, δ): 4.05 (s, 2H), 6.99 (s, 1H),7.37–7.56 (m, 6H), 7.67 (dd, J=1.2 Hz, 6.0 Hz, 2H), 7.74 (s, 1H), 7.98(dd, J=1.5 Hz, 4.5 Hz, 2H), 8.68 (dd, J=1.5 Hz, 4.5 Hz, 2H), 12.91 (br,1H).

Example 97 Preparation of2-(4-hydroxyphenyl)-6-(4-pyridyl)pyrimidin-4-one (Compound 416)

Melting Point: >300° C. NMR (DMSO-d₆, δ): 6.87 (d, J=8.7 Hz, 2H), 6.96(s, 1H), 8.05–8.14 (m, 4H), 8.69 (dd, J=1.5 Hz, 6.0 Hz, 2H), 10.25 (br,1H), 12.66 (br, 1H).

Test Example: Inhibitory Activity of the Medicament of the PresentInvention Against P-GS1 Phosphorylation by Bovine Cerebral TPK1

A mixture containing 100 mM MES-sodium hydroxide (pH 6.5), 1 mMmagnesium acetate, 0.5 mM EGTA, 5 mM β-mercaptoethanol, 0.02% Tween 20,10% glycerol, 12 μg/ml P-GS1, 41.7 μM [γ-³²P] ATP (68 kBq/ml), bovinecerebral TPK1 and a compound shown in Table (a final mixture contained1.7% DMSO deriving from a solution of a test compound prepared in thepresence of 10% DMSO) was used as a reaction system. The phosphorylationwas started by adding ATP, and the reaction was conducted at 25° C. for2 hours, and then stopped by adding 21% perchloric acid on ice cooling.The reaction mixture was centrifuged at 12,000 rpm for 5 minutes andadsorbed on P81 paper (Whatmann), and then the paper was washed fourtimes with 75 mM phosphoric acid, three times with water and once withacetone. The paper was dried, and the residual radioactivity wasmeasured using a liquid scintillation counter. The results are shown inthe table below. The test compound markedly inhibited the P-GS1phosphorylation by TPK1. The results strongly suggest that themedicaments of the present invention inhibit the TPK1 activity, therebysuppress the Aβ neurotoxicity and the PHF formation, and that themedicaments of the present invention are effective for preventive and/ortherapeutic treatment of Alzheimer disease and the above-mentioneddiseases.

TABLE 2 Example (Compound No.) IC₅₀ (μM) 1 (125) 2.3 2 (1) 3.0 5 (4) 2.16 (5) 1.3 7 (6) 2.4 12 (35) 1.8 14 (38) 4.0 15 (39) 2.2 16 (40) 4.8 19(51) 8.7 22 (60) 6.2 24 (64) 5.3 27 (75) 3.3 28 (77) 1.3 29 (78) 1.4 31(80) 2.9 33 (86) 5.5 35 (93) 8.9 36 (94) 0.50 37 (124) 3.8 38 (126) 1.842 (150) 7.6 43 (157) 5.7 44 (169) 3.7 68 (84) 1.3 69 (141) 2.5 71 (170)1.1 79 (404) 2.8 80 (397) 1.1 82 (142) 4.3 83 (33) 2.8 84 (440) 1.1 85(171) 0.96 86 (401) 10 87 (140) 2.6 88 (436) 1.4 89 (428) 2.3 90 (434)6.3 91 (421) 1.6 92 (168) 1.6 93 (430) 1.8 96 (379) 0.77 97 (416) 1.7

Formulation Example

(1) Tablets

The ingredients below were mixed by an ordinary method and compressed byusing a conventional apparatus.

Compound of Example 1 30 mg Crystalline cellulose 60 mg Corn starch 100mg Lactose 200 mg Magnesium stearate 4 mg

(2) Soft Capsules

The ingredients below were mixed by an ordinary method and filled insoft capsules.

Compound of Example 1  30 mg Olive oil 300 mg Lecithin  20 mg

(3) Parenteral Preparations

The ingredients below were mixed by an ordinary method to prepareinjections contained in a 1 ml ample.

Compound of Example 27 3 mg Sodium chloride 4 mg Distilled water forinfection 1 ml

INDUSTRIAL APPLICABILITY

The compounds of the present invention have TPK1 inhibitory activity andare useful as an active ingredient of a medicament for preventive and/ortherapeutic treatment of diseases caused by abnormal advance of TPK1such as Alzheimer disease.

1. A pyrimidone compound represented by formula (I) or apharmaceutically acceptable salt thereof:

wherein R¹ represents a group represented by —N(R⁴)—W—R⁵ wherein R⁴represents a hydrogen atom; R⁵ represents a C₁–C₁₈ alkyl group which maybe substituted, a C₃–C₁₈ alkenyl group which may be substituted, aC₃–C₁₈ alkynyl group which may be substituted, a C₃–C₈ cycloalkyl groupwhich may be substituted, or a C₆–C₁₄ aryl group which may besubstituted, and symbol “W” represents a single bond, a carbonyl group,a sulfonyl group, NH or a nitrogen atom substituted with a C₁–C₁₈ alkylgroup which may be substituted; R² represents a hydrogen atom; and R³represents a 4-pyridyl group which may be substituted.
 2. The pyrimidonecompound or the pharmaceutically acceptable salt thereof according toclaim 1 wherein R⁵ represents a C₁–C₁₈ alkyl group substituted with aC₆–C₁₀ aryl.
 3. The pyrimidone compound or the pharmaceuticallyacceptable salt thereof according to claim 1 wherein R² represents ahydrogen atom.
 4. The pyrimidone compound or the pharmaceuticallyacceptable salt thereof according to claim 1 wherein the symbol “W”represents a single bond or a carbonyl group.
 5. The pyrimidone compoundor the pharmaceutically acceptable salt thereof according to claim 4wherein the symbol “W” represents a single bond.
 6. A pyrimidonecompound represented by formula (I) or a pharmaceutically acceptablesalt thereof:

wherein R¹ represents a group represented by —N(R⁴)—W—R⁵ wherein R⁴represents a hydrogen atom, a C₁–C₁₈ alkyl group which may besubstituted, a C₃–C₁₈ alkenyl group which may be substituted, a C₃–C₁₈alkynyl group which may be substituted, a C₃–C₈ cycloalkyl group whichmay be substituted, or a C₆–C₁₄ aryl group which may be substituted, R⁵represents an alkyl group which may be substituted, said alkyl groupbeing one of ethyl group, n-propyl group, isopropyl group, n-butylgroup, isobutyl group, sec-butyl group, tert-butyl group, n-pentylgroup, isopentyl group, neopentyl group, 1,1-dimethylpropyl group,n-hexyl group, isohexyl group, a linear or branched heptyl group, octylgroup, nonyl group, decyl group, undecyl group, dodecyl group, tridecylgroup, tetradecyl group, pentadecyl group or octadecyl group, a C₃–C₁₈alkenyl group which may be substituted, a C₃–C₁₈ alkynyl group which maybe substituted, a C₃–C₈ cycloalkyl group which may be substituted, or aC₆–C₁₄ aryl group which may be substituted, and symbol “W” represents asingle bond, a carbonyl group, a sulfonyl group, NH or a nitrogen atomsubstituted with a C₁–C₁₈ alkyl group which may be substituted; R²represents a hydrogen atom or a halogen atom; and R³ represents a4-pyridyl group which may be substituted.
 7. The pyrimidone compound orthe pharmaceutically acceptable salt thereof according to claim 6wherein R² represents a hydrogen atom.
 8. The pyrimidone compound or thepharmaceutically acceptable salt thereof according to claim 6 whereinthe symbol “W” represents a single bond or a carbonyl group.
 9. Thepyrimidone compound or the pharmaceutically acceptable salt thereofaccording to claim 8 wherein the symbol “W” represents a single bond.10. The pyrimidone compound or a pharmaceutically acceptable saltthereof according to claim 6 wherein R¹ represents N,N-diethylaminogroup, N,N-dipropylamino group, N-benzyl-N-methylamino group,N-isobutyl-N-methylamino group, N-benzylamino group,N-(3-hydroxypropyl)amino group, N-cyclohexylmethylamino group,N-phenylamino group, N-(4-ethylphenyl)amino group,N-(3-bromophenyl)amino group of N-(3-methoxyphenyl)amino group.
 11. Apyrimidone compound which is selected from the group consisting of:2-(N-phenylamino)-6-(4-pyridyl)pyrimidin-4-one,2-(N,N-diethylamino)-6-(4-pyridyl)pyrimidin-4-one,2-(N,N-dipropylamino)-6-(4-pyridyl)pyrimidin-4-one,2-(N-benzylamino)-6-(4-pyridyl)pyrimidin-4-one,2-(N-benzyl-N-methylamino)-6-(4-pyridyl)pyrimidin-4-one,2-(N-(3-bromophenyl)amino)-6-(4-pyridyl)pyrimidin-4-one,2-(N-(4-ethylphenyl)amino)-6-(4-pyridyl)pyrimidin-4-one,2-(N-(3-methoxyphenyl)amino)-6-(4-pyridyl)pyrimidin-4-one,2-(N-cyclohexylmethylamino)-6-(4-pyridyl)pyrimidin-4-one, and2-(N-isobutyl-N-methylamino)-6-(4pyridyl)pyrimidin-4-one, or apharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition comprising as an active ingredient a substance selected fromthe pyrimidone compound or a pharmaceutically acceptable salt thereofaccording to claim
 1. 13. A pharmaceutical composition comprising as anactive ingredient a substance selected from the pyrimidone compound or apharmaceutically acceptable salt thereof according to claim
 6. 14. Amethod for therapeutic treatment of Alzheimer disease, which comprisesadministering to a patient a therapeutically effective amount of asubstance selected from a pyrimidone compound represented by formula (I)or a pharmaceutically acceptable salt thereof:

wherein R¹ represents a group represented by —N(R⁴)—W—R⁵ wherein R⁴ andR⁵ independently represent a hydrogen atom, a C₁–C₁₈ alkyl group whichmay be substituted, a C₃–C₁₈ alkenyl group which may be substituted, aC₃–C₁₈ alkynyl group which may be substituted, a C₃–C₈ cycloalkyl groupwhich may be substituted, or a C₆–C₁₄ aryl group which may besubstituted, and symbol “W” represents a single bond, a carbonyl group,a sulfonyl group, NH or a nitrogen atom substituted with a C₁–C₁₈ alkylgroup which may be substituted; R² represents a hydrogen atom or ahalogen atom; and R³ represents a pyridyl group which may besubstituted.